Vanilloid receptor ligands, pharmaceutical compositions containing them, process for making them, and use thereof for treating pain and other conditions

ABSTRACT

Vanilloid receptor ligand compounds corresponding to formula I: 
                         
a process for producing such compounds, pharmaceutical compositions containing them, and the use of such compounds to treat pain and various other vanilloid receptor mediated conditions.

The present invention relates to novel vanilloid receptor ligands, toprocesses for the production thereof, to medicinal drugs containing saidcompounds and to the use of said compounds for the production ofmedicinal drugs.

The treatment of pain, particularly neuropathic pain, is of greatsignificance in the medical field. There is a global need for effectivepain therapies. The urgent need for action to provide a patient-friendlyund targeted treatment of chronic and non-chronic states of pain, thisbeing taken to mean the successful und satisfactory treatment of painfor patients, is documented by the large number of scientific paperswhich have recently appeared in the field of applied analgesics or inbasic research concerning nociception.

A suitable starting point for the treatment of pain; particularly ofpain selected from the group consisting of acute pain, chronic pain,neuropathic pain, and visceral pain and more preferably neuropathicpain; is the vanilloid receptor of subtype 1 (VR1/TRPV1), frequentlyalso designated as the capsaicin receptor. This receptor is stimulated,inter alia, by vanilloids such as capsaicin, heat, and protons and playsa central part in the generation of pain. Furthermore, it is significantfor a large number of other physiological and pathophysiologicalprocesses such as migraine; states of depression; neurodegenerativedisorders; cognitive disorders; anxiety; epilepsy; coughing; diarrhea;pruritus; inflammations; disorders of the cardiovascular system; foodintake disorders; medicine addiction; medicine abuse and, in particular,urinary incontinence.

It is thus an object of the invention to provide novel compounds whichare particularly suitable for use as pharmacologically active substancesin medicinal drugs, preferably in medicinal drugs for treatment ofdisorders or diseases that are at least partially mediated by vanilloidreceptors 1 (VR1/TRPV1 receptors). It has now been found, surprisingly,that the substituted compounds of the general formula I stated belowshow excellent affinity to the vanilloid receptor of subtype 1(VR1/TRPV1 receptor) and are therefore particularly suitable for theprophylaxis and/or treatment of disorders or diseases which are at leastpartially mediated by vanilloid receptors 1 (VR1/TRPV1). The substitutedcompounds corresponding to the following formula I also showanti-inflammatory activity.

It is thus at object of the present invention to provide substitutedcompounds of the general formula I,

in which

-   n stands for 0, 1, 2, 3, or 4;-   R¹ stands for H; F; Cl; Br; I; —SF₅; —NO₂; —CN; —NH₂; —OH; —SH;    —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H;    —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —N═C(NH₂)₂;    —N═C(NHR¹⁰)—(NHR¹¹); —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰;    —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶;    or —S(═O)₂—R²⁷ or for a linear or branched, saturated or    unsaturated, unsubstituted or at least monosubstituted aliphatic    C₁₋₁₀ radical;-   R² stands for H; F; Cl; Br; I; —SF₅; —NO₂; —CN; —NH₂; —OH; —SH;    —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H;    —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —N═C(NH₂)₂;    —N═C(NHR¹⁰)—(NHR¹¹); —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰;    —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶;    or —S(═O)₂—R²⁷ or for a linear or branched, saturated or    unsaturated, unsubstituted or at least monosubstituted aliphatic    C₁₋₁₀ radical;-   R³ stands for H; F; Cl; Br; I; —SF₅; —NO₂; —CN; —NH₂; —OH; —SH;    —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H;    —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —N═C(NH₂)₂;    —N═C(NHR¹⁰)—(NHR¹¹); —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰;    —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶;    or —S(═O)₂—R²⁷ or for a linear or branched, saturated or    unsaturated, unsubstituted or at least monosubstituted aliphatic    C₁₋₁₀ radical;-   R⁴ stands for H; F; Cl; Br; I; —SF₅; —NO₂; —CN; —NH₂; —OH; —SH;    —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H;    —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —N═C(NH₂)₂;    —N═C(NHR¹⁰)—(NHR¹¹); —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰;    —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶;    or —S(═O)₂—R²⁷ or for a linear or branched, saturated or    unsaturated, unsubstituted or at least monosubstituted aliphatic    C₁₋₁₀ radical;-   R⁵ stands for H; F; Cl; Br; I; —SF₅; —NO₂; —CN; —NH₂; —OH; —SH;    —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H;    —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —N═C(NH₂)₂;    —N═C(NHR¹⁰)—(NHR¹¹); —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰;    —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶;    or —S(═O)₂—R²⁷ or for a linear or branched, saturated or    unsaturated, unsubstituted or at least monosubstituted aliphatic    C₁₋₁₀ radical;-   R⁶ stands in each case for hydrogen or for a linear or branched,    saturated or unsaturated, unsubstituted or at least monosubstituted    aliphatic C₁₋₁₀ radical;-   R⁷ stands for hydrogen or —OH;-   or-   R⁶ and R⁷ form, together with the interconnecting carbon atom as    ring member, a saturated or unsaturated, unsubstituted or at least    monosubstituted three-membered, four-membered, five-membered, or    six-membered cycloaliphatic radical;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; —O—CFH₂; —O—CF₂H; —CFH₂; —CF₂H; or    for an unsubstituted or at least monosubstituted tert-butyl radical;-   T stands for C—R³⁵ and U stands for C—R³⁶ and V stands for N and W    stands for C—R³⁸; or-   T stands for C—R³⁵ and U stands for N and V stands for C—R³⁷ and W    stands for C—R³⁸; or-   T stands for N and U stands for C—R³⁶ and V stands for C—R³⁷ and W    stands for C—R³⁸; or-   T stands for N and U stands for N and V stands for C—R³⁷ and W    stands for C—R³⁸; or-   T stands for N and U stands for C—R³⁶ and V stands for N and W    stands for C—R³⁸; or-   T stands for C—R³⁵ and U stands for N and V stands for N and W    stands for C—R³⁸; or-   T stands for C—R³⁵ and U stands for C—R³⁶ and V stands for C—R³⁷ and    W stands for C—R³⁸;-   R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²²,    R²³, R²⁴, R²⁵, R²⁶ and R²⁷ each independently-    stand for a linear or branched, saturated or unsaturated,    unsubstituted or at least monosubstituted aliphatic C₁₋₁₀ radical;-    for an unsaturated or saturated, unsubstituted or at least    monosubstituted, three-membered, four-membered, five-membered,    six-membered, seven-membered, eight-membered, or nine-membered    cycloaliphatic radical optionally containing at least one heteroatom    as ring member, which can be condensed with a saturated or    unsaturated, unsubstituted or at least monosubstituted monocyclic or    polycyclic ring system and/or can be bonded via a linear or    branched, unsubstituted or at least monosubstituted C₁₋₆ alkylene    group or two to six-membered heteroalkylene group;-    or for an unsubstituted or at least monosubstituted five-membered    to fourteen-membered aryl radical or heteroaryl radical, which can    be condensed with a saturated or unsaturated, unsubstituted or at    least monosubstituted monocyclic or polycyclic ring system and/or    can be bonded via a linear or branched, unsubstituted or at least    monosubstituted C₁₋₆ alkylene group or two to six-membered    heteroalkylene group;-   R³⁵, R³⁶, and R³⁷ each independently-    stand for H; F; Cl; Br; I; —SF₅; —NO₂; —CF₃; and —CN; —NH₂; —OH;    —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; and    —S(═O)₂—OH; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷;    —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰; —S(═O)₂—NHR²¹; and —S(═O)₂—NR²²R²³;    —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶; —S(═O)²R²⁷-    for a linear or branched, saturated or unsaturated, unsubstituted    or at least monosubstituted aliphatic C₁₋₁₀ radical;-    or for an unsubstituted or at least monosubstituted five-membered    to fourteen-membered aryl radical or heteroaryl radical, which can    be condensed with a saturated or unsaturated, unsubstituted or at    least monosubstituted monocyclic or polycyclic ring system and/or    can be bonded via a linear or branched, unsubstituted or at least    monosubstituted C₁₋₆ alkylene group or C₂₋₆ alkenylene group or    C₂₋₆-alkynylene group;-   R³⁸ stands for F; Cl; Br; I; —SF₅; —NO₂; —CF₃; —CF₂Cl; —CN; —NH₂;    —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; and —C(═O)—OH;    —C(═O)—H; —S(═O)₂—OH; —NHR³⁹; —NR⁴⁰R⁴¹; —OR⁴²; —SR⁴³; —C(═O)—NHR⁴⁴;    —C(═O)—NR⁴⁵R⁴⁶; and —S(═O)₂—NHR⁴⁷; —S(═O)₂—NR⁴⁸R⁴⁹; —C(═O)—OR⁵⁰;    —C(═O)—R⁵¹; —S(═O)—R⁵²; —S(═O)₂—R⁵³; —C(═NH)—NH₂; —C(═NH)—NH—R⁵⁴;    —N═C(NH₂)₂; and —N═C(NHR⁵⁵)—(NHR⁵⁶);-    for a linear or branched, saturated or unsaturated, unsubstituted    or at least monosubstituted aliphatic C₁₋₁₀ radical;-    for an unsaturated or saturated, unsubstituted or at least    monosubstituted three-membered, four-membered, five-membered,    six-membered, seven-membered, eight-membered, or nine-membered    cycloaliphatic radical optionally exhibiting at least one heteroatom    as ring member, each of which is bonded to the parent structure over    a carbon atom in the ring of the cycloaliphatic radical and is    condensed with a saturated or unsaturated, unsubstituted or at least    monosubstituted monocyclic or polycyclic ring system and/or can be    bonded via a linear or branched, unsubstituted or at least    monosubstituted C₁₋₆ alkylene group or C₂₋₆ alkenylene group or C₂₋₆    alkynylene group;-    or for an unsubstituted or at least monosubstituted five-membered    to fourteen-membered aryl radical or heteroaryl radical, which can    be condensed with a saturated or unsaturated, unsubstituted or at    least monosubstituted monocyclic or polycyclic ring system and/or    can be bonded via a linear or branched, unsubstituted or at least    monosubstituted C₁₋₆ alkylene group or C₂₋₆ alkenylene group or    C₂₋₆-alkynylene group;-   R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹,    R⁵², R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ each independently-    stand for a linear or branched, saturated or unsaturated,    unsubstituted or at least monosubstituted aliphatic C₁₋₁₀ radical;-    for an unsaturated or saturated, unsubstituted or at least    monosubstituted, three-membered, four-membered, five-membered,    six-membered, seven-membered, eight-membered, or nine-membered    cycloaliphatic radical optionally containing at least one heteroatom    as ring member, which can be condensed with a saturated or    unsaturated, unsubstituted or at least monosubstituted monocyclic or    polycyclic ring system and/or can be bonded via a linear or    branched, unsubstituted or at least monosubstituted C₁₋₆ alkylene    group or two to six-membered heteroalkylene group;-    or for an unsubstituted or at least monosubstituted five-membered    to fourteen-membered aryl radical or heteroaryl radical, which can    be condensed with a saturated or unsaturated, unsubstituted or at    least monosubstituted monocyclic or polycyclic ring system and/or    can be bonded via a linear or branched, unsubstituted or at least    monosubstituted C₁₋₆ alkylene group or two to six-membered    heteroalkylene group;-   or-   R⁴⁰ and R⁴¹ form, together with the interconnecting nitrogen atom as    ring member, a saturated or unsaturated four-membered,    five-membered, six-membered, seven-membered, eight-membered, or    nine-membered heterocycloaliphatic radical, which is unsubstituted    or substituted by 1, 2, 3, 4, or 5 radicals R⁵⁷ and optionally    exhibits at least one further heteroatom as ring member, and which    can be condensed with a saturated or unsaturated, unsubstituted or    at least monosubstituted monocyclic or polycyclic ring system;-   R⁵⁷ stands for —NHR⁵⁸, —NR⁵⁹R⁶⁰, or for a linear or branched,    saturated or unsaturated, unsubstituted or at least monosubstituted    aliphatic C₁₋₁₀ radical;-   R⁵⁸, R⁵⁹, and R⁶⁰ each independently-    stand for —C(═O)—R⁶¹;-    for a linear or branched, saturated or unsaturated, unsubstituted    or at least monosubstituted aliphatic C₁₋₁₀ radical-    or for an unsubstituted or at least monosubstituted five-membered    to fourteen-membered aryl radical or heteroaryl radical, which can    be condensed with a saturated or unsaturated, unsubstituted or at    least monosubstituted monocyclic or polycyclic ring system and/or    can be bonded via a linear or branched, unsubstituted or at least    monosubstituted C₁₋₆ alkylene group or C₂₋₆ alkenylene group or C₂₋₆    alkynylene group;-   and-   R⁶¹ stands for a linear or branched, saturated or unsaturated,    unsubstituted or at least monosubstituted aliphatic C₁₋₁₀ radical;    each optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers thereof, the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or each in the form of corresponding salts,    or each in the form of corresponding solvates;    wherein    the aforementioned aliphatic C₁₋₁₀ radicals and tert-butyl radicals    can each be optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9    substituents independently selected from the group consisting of F,    Cl, Br, I, —CN, —NO₂, —OH, —NH₂, —SH, —O(C₁₋₅ alkyl), —S(C₁₋₅    alkyl), —NH(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)-(C₁₋₅ alkyl), —C(═O)—O—(C₁₋₅    alkyl), —O—C(═O)—(C₁₋₅ alkyl), —O-phenyl, phenyl, —OCF₃, and —SCF₃;    the aforementioned two to six-membered heteroalkylene groups, C₁₋₆    alkylene groups, and C₂₋₆ alkenylene groups and C₂₋₆ alkynylene    groups can each be optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8,    or 9 substituents independently selected from the group consisting    of F, Cl, Br, I, —CN, —NO₂, —OH, —NH₂, —SH, —O(C₁₋₅ alkyl), —S(C₁₋₅    alkyl), —NH(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)-(C₁₋₅ alkyl), —OCF₃, and    —SCF₃;    the aforementioned heteroalkylene groups each optionally exhibit 1,    2, or 3 heteroatom(s) independently selected from the group    consisting of oxygen, sulfur, and nitrogen (NH) as link(s);    the aforementioned (hetero)cycloaliphatic radicals are optionally    each substituted by 1, 2, 3, 4, or 5 substituents independently    selected from the group consisting of —(C₁₋₆ alkylene)—OH, ═CH₂,    —O—(C₁₋₅ alkylene)oxetanyl, —(C₁₋₅ alkylene)—O—(C₁₋₅    alkylene)oxetanyl, —CH₂—NH—(C₁₋₅ alkyl), —CH₂—N(C₁₋₅ alkyl)₂,    —N[C(═O)—(C₁₋₅ alkyl)]phenyl, —CH₂—O—(C₁₋₅ alkyl), oxo (═O), thioxo    (═S), F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—(C₁₋₅ alkyl),    —O—C(═O)—(C₁₋₅ alkyl), —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—(C₁₋₅    alkyl), —(C₁₋₅ alkyl), —C(═O)—(C₁₋₅ alkyl), —C(═O)—OH,    —C(═O)—O—(C₁₋₅ alkyl), —NH—(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)₂,    —NH-phenyl, —N(C₁₋₅ alkyl)phenyl, cyclohexyl, cyclopentyl,    (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl,    thiophenyl, phenethyl, piperidinyl, pyrrolidinyl, —(CH₂)pyridinyl,    pyridinyl, —O-phenyl, —O-benzyl, phenyl, and benzyl, and the cyclic    moiety of the radicals oxetanyl, (4,5)-dihydroisoxazolyl, thiazolyl,    (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, —N[C(═O)—(C₁₋₅    alkyl)]phenyl, —NH-phenyl, —N(C₁₋₅ alkyl)phenyl, —(CH₂)pyridinyl,    pyridinyl, —O-phenyl, —O-benzyl, phenyl, and benzyl can each be    substituted by 1, 2, 3, 4, or 5 substituents independently selected    from the group consisting of F, Cl, Br, —OH, —CF₃, —SF₅, —CN, —NO₂,    —(C₁₋₅ alkyl, —O—(C₁₋₅ alkyl), —O—CF₃, —S—CF₃, phenyl, and    —O-benzyl,    and, unless otherwise stated, the aforementioned    (hetero)cycloaliphatic radicals can each optionally exhibit 1, 2, or    3 (further) heteroatom(s) independently selected from the group    consisting of oxygen, nitrogen, and sulfur;    the rings of the aforementioned monocyclic or polycyclic ring    systems can each be optionally substituted by 1, 2, 3, 4, or 5    substituents independently selected from the group consisting of oxo    (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—(C₁₋₅    alkyl), —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—(C₁₋₅ alkyl), —(C₁₋₅    alkyl), —C(═O)—(C₁₋₅ alkyl), —C(═O)—OH, —C(═O)—O—(C₁₋₅ alkyl),    —NH—(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)₂, —O-phenyl, —O-benzyl, phenyl, and    benzyl, and the cyclic moiety of the radicals —O-phenyl, —O-benzyl,    phenyl, and benzyl can each be substituted by 1, 2, 3, 4, or 5    substituents independently selected from the group consisting of F,    Cl, Br, —OH, —CF₃, —SF₅, —CN, —NO₂, —(C₁₋₅ alkyl), —O—(C₁₋₅ alkyl),    —O—CF₃, —S—CF₃, phenyl, and —O-benzyl,    and the rings of the aforementioned monocyclic or polycyclic ring    systems are each five-membered, six-membered, or seven-membered and    can each optionally exhibit 1, 2, 3, 4, or 5 heteroatom(s) as ring    member(s), which are independently selected from the group    consisting of oxygen, nitrogen, and sulfur;    and the aforementioned aryl radicals or heteroaryl radicals can each    be optionally substituted by 1, 2, 3, 4, or 5 substituents    independently selected from the group consisting of F, Cl, Br, I,    —CN, —CF₃, —SF₅, —OH, —O—(C₁₋₅ alkyl), —NH₂, —NO₂, —O—CF₃, —S—CF₃,    —SH, —S—(C₁₋₅ alkyl), —(C₁₋₅ alkyl), —C(═O)—OH, —C(═O)—O—(C₁₋₅    alkyl), —NH—(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)₂, —NH—S(═O)₂—(C₁₋₅ alkyl),    —NH—C(═O)—O—(C₁₋₅ alkyl), —C(═O)—H, —C(═O)—(C₁₋₅ alkyl), —C(═O)—NH₂,    —C(═O)—NH—(C₁₋₅ alkyl), —C(═O)—N—(C₁₋₅ alkyl)₂, —O-phenyl,    —O-benzyl, phenyl, and benzyl, and the cyclic moiety of the radicals    —O-phenyl, —O-benzyl, phenyl, and benzyl can each be substituted by    1, 2, 3, 4, or 5 substituents independently selected from the group    consisting of F, Cl, Br, —OH, —CF₃, —SF₅, —CN, —NO₂, —(C₁₋₅ alkyl),    —O—(C₁₋₅ alkyl), —O—CF₃, —S—CF₃, phenyl, and —O-benzyl, and    the aforementioned heteroaryl radicals can each optionally exhibit    1, 2, 3, 4, or 5 heteroatom(s) independently selected from the group    consisting of oxygen, nitrogen, and sulfur as ring member(s).

The term “heteroalkylene” designates an alkylene chain in which one ormore carbons have each been replaced by a heteroatom independentlyselected from the group consisting of oxygen, sulfur and nitrogen (NH).Heteroalkylene groups can preferably contain 1, 2, or 3 heteroatom(s)and more preferably one heteroatom, independently selected from thegroup consisting of oxygen, sulfur and nitrogen (NH), as link(s).Heteroalkylene groups can preferably be two to six-membered and morepreferably two or three-membered.

Examples of heteroalkylene groups include —CH₂—CH₂—O—CH₂—,—CH₂—CH(CH₃)—O—CH₂—, —(CH₂)—O—, —(CH₂)₂—O—, —(CH₂)₃—O—, —(CH₂)₄—O—,—O—(CH₂)—, —O—(CH₂)₂—, —O—(CH₂)₃—, —O—(CH₂)₄—, —C(C₂H₅)—(H)—O—,—O—C(C₂H₅)—(H)—, —CH₂—O—CH₂—, —CH₂—S—CH₂—, —CH₂—NH—CH₂—, —CH₂—NH—, and—CH₂—CH₂—NH—CH₂—CH₂.

If one or more of the aforementioned substituents exhibit a linear orbranched C₁₋₆ alkylene group, these can be preferably selected from thegroup consisting of —(CH₂)—, —(CH₂)₂—, —C(H)—(CH₃)—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, —C(H)—(C(H)—(CH₃)₂)—, and —C(C₂H₅)—(H)—.

Saturated or unsaturated C₁₋₁₀ aliphatic radicals can stand for a C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl radical. C₂₋₁₀ alkenyl radicalshave at least one and preferably 1, 2, 3, or 4 C—C double bonds andC₂₋₁₀ alkynyl radicals at least one and preferably 1, 2, 3, or 4 C—Ctriple bonds.

Preference is given to C₁₋₁₀ alkyl radicals selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, 3-methylbut-1-yl, 2-pentyl, 3-pentyl,sec-pentyl, neopentyl, 4-methylpent-1-yl, (3,3)-dimethylbut-1-yl,n-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, n-nonyl,2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, and (2,6)-dimethylhept-4-yl, whichcan be optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9substituents independently selected from the group consisting of—O-phenyl, —O—C(═O)—CH₃, —O—C(═O)—C₂H₅, —O—C(═O)—CH(CH₃)₂,—O—C(═O)—C(CH₃)₃, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂,—C(═O)—O—C(CH₃)₃, F, Cl, Br, I, —CN, —NO₂, —OH, —NH₂, —SH, —O—CH₃,—O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂,—S—C(CH₃)₃, —NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂,—N(CH₃)—(C₂H₅), —OCF₃, and —SCF₃.

In another preferred embodiment, C₂₋₁₀ alkenyl radicals are selectedfrom the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-methylpropen-1-yl, 3-methylbut-2-en-1-yl,(3,3)-dimethylbut-1-enyl, 2-methylbuten-2-yl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-hexenyl, 1-heptenyl, and 1-octenyl, which canbe optionally substituted by 1, 2, or 3 substituents independentlyselected from the group consisting of F, Cl, Br, I, —CN, —NO₂, —OH,—NH₂, —SH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —S—CH₃, —S—C₂H₅,—S—CH(CH₃)₂, —S—C(CH₃)₃, —NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂,—N(C₂H₅)₂, —N(CH₃)—(C₂H₅), —OCF₃, and —SCF₃.

Preference is also given to C₂₋₁₀ alkynyl radicals selected from thegroup consisting of (3,3)-dimethylbut-1-ynyl, 4-methylpent-1-ynyl,1-hexynyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl, which canbe optionally substituted by 1, 2, or 3 substituents independentlyselected from the group consisting of F, Cl, Br, I, —CN, —NO₂, —OH,—NH₂, —SH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —S—CH₃, —S—C₂H₅,—S—CH(CH₃)₂, —S—C(CH₃)₃, —NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂,—N(C₂H₅)₂, —N(CH₃)—(C₂H₅), —OCF₃, and —SCF₃.

Particularly preferred optionally substituted C₁₋₁₀ aliphatic radicalsare selected from the group consisting of methyl, —CF₃, —CHF₂, —CH₂F,—CF₂Cl, —CCl₂F, —CCl₃, —CBr₃, —CH₂—CN, —CH₂—O—CH₃, —CH₂—O—CF₃, —CH₂—SF₃,—CH₂—NH₂, —CH₂—OH, —CH₂—SH, —CH₂—NH—CH₃, —CH₂—N(CH₃)₂, —CH₂—N(C₂H₅)₂,—CH₂—N(CH₃)—(C₂H₅), ethyl, —CF₂—CH₃, —CHF—CF₂Cl, —CF₂—CFCl₂,—CFCl—CF₂Cl, —CFCl—CFCl₂, —CH₂—CH₂—NH₂, —CH₂—CH₂—OH, —CH₂—CH₂—SH,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)₂, —CH₂—CH₂—N(C₂H₅)₂,—CH₂—CH₂—N(CH₃)—(C₂H₅), —CH₂—CF₃, —C₂F₅, —CH₂—CCl₃, —CH₂—CBr₃,—CH₂—CH₂—CN, n-propyl, —CH₂—CH₂—CH₂—OH, —CH₂—CH₂—CH₂—SH,—CH₂—CH₂—CH₂—NH₂, —CH₂—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—CH₂—N(CH₃)₂,—CH₂—CH₂—CH₂—N(C₂H₅)₂, —CH₂—CH₂—CH₂—N(CH₃)—(C₂H₅), —CH₂—CH₂—O—CH₃,—CF₂—CF₂—CF₃, —CF(CF₃)₂, isopropyl, —CH₂—CH₂—CH₂—CN, —CH₂—O—CH₂—CH₃,—CH₂—CH₂—SF₃, —CH₂—CH₂—OCF₃, —CH(CH₃)—(O—CH₃), —CH(CH₃)—(S—CH₃),n-butyl, —CF₂—CF₂—CF₂—CF₃, —CH₂—CH₂—CH₂—CH₂—CN, —CH₂—CH₂—CH₂—CF₃,—CH₂—CH₂—CH₂—CH₂—CF₃, —CH₂—O—C(═O)—CH₃, —CH₂—O—C(═O)—C₂H₅,—CH₂—O—C(═O)—CH(CH₃)₂, —CH₂—O—C(═O)—C(CH₃)₃, —CH₂—C(═O)—O—CH₃,—CH₂—C(═O)—O—C₂H₅, —CH₂—C(═O)—O—C(CH₃)₃, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—O—C₂H₅, —CH₂—CH₂—O-phenyl, —CH₂—CH₂—CH₂—O—CH₃, sec-butyl,isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, vinyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methylbutene-2-yl, (1,1,2)-trifluoro-1-butenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, —CF═CF₂, —CCl═CCl₂, —CH₂—CF═CF₂,—CH₂—CCl═CCl₂, —C≡C—I, —C≡C—, and —C≡C—Cl.

If one or more of the aforementioned substituents stand for a(hetero)cycloaliphatic radical, which can be optionally condensed with asaturated or unsaturated, unsubstituted or at least monosubstitutedmonocyclic or polycyclic ring system, this can preferably be selectedfrom the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl,tetrahydropyranyl, oxetanyl, (1,2,3,6)-tetrahydropyridinyl, azepanyl,azocanyl, diazepanyl, dithiolanyl,(1,3,4,5)-tetrahydropyrido[4.3-b]indolyl,(3,4)-dihydro-1H-isoquinolinyl, (1,3,4,9)-tetrahydro[b]carbolinyl, and(1,3)-thiazolidinyl.

As examples of suitable (hetero)cycloaliphatic radicals, which can beunsubstituted or monosubstituted or polysubstituted and are condensedwith a monocyclic or bicyclic ring system, there may be mentioned(4,5,6,7)-tetrahydroisoxazolo[5.4-c]pyridinyl, (2,3)-dihydro-1H-indenyl,3-azabicyclo[3.1.1]heptyl, 3-acabicyclo[3.2.1]octyl,6-azabicyclo[3.3.1]heptyl, 8-acabicyclo[3.2.1]octyl, isoindolyl,indolyl, (1,2,3,4)-tetrahydroquinolinyl,(1,2,3,4)-tetrahydroisoquinolinyl, (2,3)-dihydro-1H-isoindolyl,(1,2,3,4)-tetrahydronaphthyl, (2,3)-dihydrobenzo[1.4]dioxinyl,benzo[1.3]dioxolyl, (1,4)-benzodioxanyl,(2,3)-dihydrothieno[3.4-b][1.4]dioxinyl,(3,4)-dihydro-2H-benzo[1,4]oxazinyl, octahydro-1H-isoindolyl, andoctahydropyrrolo[3.4-c]pyrrolyl.

(Hetero)cycloaliphatic radicals can form, within the scope of thepresent invention, a spirocyclic radical with another(hetero)cycloaliphatic radical via a carbon atom common to both rings.

Examples of suitable spirocyclic radicals include a 6-azaspiro[2.5]octylradical, an 8-azaspiro[4.5]decyl radical and a1-oxa-2,8-diazaspiro[4.5]dec-2-enyl radical. More preferably the(hetero)cycloaliphatic radicals can each be optionally substituted by 1,2, 3, 4, or 5 substituents independently selected from the groupconsisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH,—O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —NH₂, —NO₂, —O—CF₃, —S—CF₃,—SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,—C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃, —C(═O)—OH,—C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂, —C(═O)—O—C(CH₃)₃,—NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(CH₃)—(C₂H₅),—CH₂—OH, —CH₂—CH₂—OH, ═CH₂, —CH₂—O—CH₂-oxetanyl, —O—CH₂-oxetanyl,—CH₂—N(CH₃)₂, —CH₂—N(C₂H₅)₂, —CH₂—NH—CH₃, —CH₂—NH—C₂H₅,—N—[C(═O)—C₂H₅]-phenyl, —N—[C(═O)—CH₃]-phenyl, —CH₂—O—CH₃,—CH₂—O—CH₂—CH₃, —NH-phenyl, —N(CH₃)phenyl, —N(C₂H₅)phenyl,—N(C₂H₅)phenyl, —O—CH₂—CH₂—CH₂—CH₃, (4,5)-dihydroisoxazolyl, thiazolyl,(1,2,5)-thiadiazolyl, thiophenyl, phenethyl, cyclohexyl, cyclopentyl,piperidinyl, pyrrolidinyl, —O—C(═O)—CH₃, —O—C(═O)—C₂H₅,—O—C(═O)—C(CH₃)₃, —(CH₂)pyridinyl, pyridinyl, —O-phenyl, —O-benzyl,phenyl, and benzyl, and the cyclic moiety of the radicals oxetanyl,(4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl,phenethyl, —N—[C(═O)—C₂H₅]phenyl, —N—[C(═O)—CH₃]phenyl, —NH-phenyl,—N(CH₃)phenyl, —N(C₂H₅)phenyl, —(CH₂)pyridinyl, pyridinyl, —O-phenyl,—O-benzyl, phenyl, and benzyl can each be substituted by 1, 2, 3, 4, or5 substituents independently selected from the group consisting of F,Cl, Br, —OH, —CF₃, —SF₅, —CN, —NO₂, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂,—O—C(CH₃)₃, —O—CF₃, —S—CF₃, phenyl, and —O-benzyl.

If one or more of the aforementioned substituents stand for an arylradical, this can preferably be selected from the group consisting ofphenyl and naphthyl (1-naphthyl and 2-naphthyl).

If one or more of the aforementioned substituents stand for a heteroarylradical, this can preferably be selected from the group consisting oftetrazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl,pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl,benzo[b]furanyl, benzo[b]thiophenyl, benzoxazolyl, benzisoxazolyl,thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl,indazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl.

Examples of suitable aryl and heteroaryl radicals, which may beunsubstituted or monosubstituted or polysubstituted and are condensedwith a monocyclic or bicyclic ring system, include isoindolyl, indolyl,(1,2,3,4)-tetrahydroquinolinyl, (1,2,3,4)-tetrahydroisoquinolinyl,(2,3)-dihydro-1H-isoindolyl, (1,2,3,4)-tetrahydronaphthyl,(2,3)-dihydrobenzo[1.4]dioxinyl,(2,3)-dihydrothieno[3.4-b][1.4]dioxinyl, benzo[1.3]dioxolyl, and(1,4)-benzodioxanyl.

More preferably, the aryl radicals or heteroaryl radicals can each beoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from the group consisting of F, Cl, Br, I, —CN, —CF₃, —SF₅,—OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —NH₂, —NO₂, —O—CF₃,—S—CF₃, —SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,—C(═O)—OH, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂,—C(═O)—O—C(CH₃)₃, —NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂,—N(CH₃)—(C₂H₅), —NH—S(═O)₂—CH₃, —NH—S(═O₂)—C₂H₅, —NH—S(═O)₂—CH(CH₃)₂,—NH—C(═O)—O—CH₃, —NH—C(═O)—O—C₂H₅, —NH—C(═O)—O—C(CH₃)₃, —C(═O)—H,—C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃, —C(═O)—NH₂,—C(═O)—NH—CH₃, —C(═O)—NH—C₂H₅, —C(═O)—N(CH₃)₂, —C(═O)—N(C₂H₅)₂,—O-phenyl, —O-benzyl, phenyl, and benzyl, and the cyclic moiety of theradicals —O-phenyl, —O-benzyl, phenyl, and benzyl can each besubstituted by 1, 2, 3, 4, or 5 substituents independently selected fromthe group consisting of F, Cl, Br, —OH, —CF₃, —SF₅, —CN, —NO₂, methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,—O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —O—CF₃, —S—CF₃, phenyl, and—O-benzyl.

If a polycyclic ring system such as a bicyclic ring system is present,the different rings can independently exhibit a different degree ofsaturation, i.e. be saturated or unsaturated. A polycyclic ring systemis preferably a bicyclic ring system.

Examples of aryl radicals condensed with a monocyclic or polycyclic ringsystem include (1,3)-benzodioxolyl and (1,4)-benzodioxanyl.

If one or more of the aforementioned substituents have a monocyclic orpolycyclic ring system, this can preferably be substituted by 1, 2, 3,4, or 5 substituents independently selected from the group consisting ofoxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—CH₃,—O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH,—S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,—C(═O)—OH, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂,—C(═O)—O—C(CH₃)₃, —NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂,—N(CH₃)—(C₂H₅), —NH—C(═O)—O—CH₃, —NH—C(═O)—O—C₂H₅, —NH—C(═O)—O—C(CH₃)₃,—C(═O)—H, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃,—C(═O)—NH₂, —C(═O)—NH—CH₃, —C(═O)-nH—C₂H₅, —C(═O)—N(CH₃)₂,—C(═O)—N(C₂H₅)₂, —O-phenyl, —O-benzyl, phenyl, and benzyl, and thecyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzylcan each be substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from the group consisting of F, Cl, Br, —OH, —CF₃, —SF₅, —CN,—NO₂, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —O—CF₃, —S—CF₃,phenyl, and —O-benzyl.

If R⁴¹ and R⁴² together with the interconnecting nitrogen atom as ringmember form a heterocycloaliphatic radical, which is substituted by 1,2, 3, 4, or 5 radicals R⁵⁷, said radicals R⁵⁷ may each be independentlyfrom one another selected from the above given meanings.

in which

-   D stands for N or CH;-   R¹ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R² stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R³ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R⁴ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R⁵ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; tert-butyl; or —C(CH₃)₂(CH₂OH);-   R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷, each independently stand for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, —CF₂—CH₃, —CH₂—CF₃, —C₂F₅, n-propyl, isopropyl,    n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl,    n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl,    (2,6)-dimethylhept-4-yl, 3-methylbutyl, n-hexyl, (3,3)-dimethylbutyl    and ethenyl;-   R⁴² stands for a radical selected from the group consisting of    methyl, —CH₂—O—CH₃, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl,    tert-butyl, n-pentyl, 3-pentyl, n-hexyl, (3,3)-dimethylbutyl,    —CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—C₂H₅, and —CH₂—CH₂—CH₂—O—CH₃;-    or for a radical selected from the group consisting of    2,3-dihydro-1H-indenyl, cyclopropyl, oxetanyl, cyclobutyl,    cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl,    tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl,    piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl,    each of which can be optionally substituted by 1, 2, 3, 4, or 5    substituents independently selected from the group consisting of    methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,    tert-butyl, and n-pentyl;    in each case optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers, or the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or in each case in the form of corresponding    salts, or in each case in the form of corresponding solvates.

Special preference is given to compounds of the general formula Ia,

in which

-   D stands for N or CH;-   R¹ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷,-   R² stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R³ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R⁴ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R⁵ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; tert-butyl; or —C(CH₃)₂(CH₂OH);-   R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently stand for a    radical selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl and ethenyl;-   R⁴² stands for a radical selected from the group consisting of    methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl;-    or for a radical selected from the group consisting of cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which    can be optionally substituted by 1, 2, 3, 4, or 5 substituents    independently selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and    n-pentyl;    in each case optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers, or the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or in each case in the form of corresponding    salts, or in each case in the form of corresponding solvates.

Very special preference is given to compounds of the general formula Ia,

in which

-   D stands for N or CH;-   R¹ stands for H; F; Cl; Br or I;-   R² stands for H; F; Cl; Br; I; methyl; —OH; —NH₂ or —OR¹⁶;-   R³ stands for H; F; Cl; Br; I; —NO₂; —OH; —NH₂; —NH—C(═O)—R¹³,    —OR¹⁶; SR¹⁷; —S(═O)—NR²²R²³ or —S(═O)—R²⁷;-   R⁴ stands for H; F; Cl; Br; I; methyl, —OH; —NH₂ or —OR¹⁶;-   R⁵ stands for H; F; Cl; Br; or I;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; tert-butyl; or —C(CH₃)₂(CH₂OH);-   R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently stand for a    radical selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl and ethenyl;-   R⁴² stands for a radical selected from the group consisting of    methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl;-    or for a radical selected from the group consisting of cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which    can be optionally substituted by 1, 2, 3, 4, or 5 substituents    independently selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and    n-pentyl;    in each case optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers, or the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or in each case in the form of corresponding    salts, or in each case in the form of corresponding solvates.

Preference is given to compounds of the general formula Ib,

in which

-   D stands for N or CH;-   R¹ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R² stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R³ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R⁴ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R⁵ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; tert-butyl; or —C(CH₃)₂(CH₂OH);-   R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently stand for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, —CF₂—CH₃, —CH₂—CF₃, —C₂F₅, n-propyl, isopropyl,    n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl,    n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl,    (2,6)-dimethylhept-4-yl, 3-methylbutyl, n-hexyl, (3,3)-dimethylbutyl    and ethenyl;-   R⁴³ stands for a radical selected from the group consisting of    methyl, —CH₂—O—CH₃, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl,    tert-butyl, n-pentyl, 3-pentyl, n-hexyl, (3,3)-dimethylbutyl,    —CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—C₂H₅, and —CH₂—CH₂—CH₂—O—CH₃;-    or for a radical selected from the group consisting of    2,3-dihydro-1H-indenyl, cyclopropyl, oxetanyl, cyclobutyl,    cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl,    tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl,    piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl,    each of which can be optionally substituted by 1, 2, 3, 4, or 5    substituents independently selected from the group consisting of    methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,    tert-butyl, and n-pentyl;    in each case optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers, or the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or in each case in the form of corresponding    salts, or in each case in the form of corresponding solvates.

Special preference is given to compounds of the general formula Ib,

in which

-   D stands for N or CH;-   R¹ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷—S(═O)₂—NR²²R²³ or —(S═O)—R²⁷,-   R² stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R³ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R⁴ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R⁵ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; tert-butyl; or —C(CH₃)₂(CH₂OH);-   R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently stand for a    radical selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl, and ethenyl;-   R⁴³ stands for a radical selected from the group consisting of    methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl;-    or for a radical selected from the group consisting of cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which    can be optionally substituted by 1, 2, 3, 4, or 5 substituents    independently selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and    n-pentyl;    in each case optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers, or the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or in each case in the form of corresponding    salts, or in each case in the form of corresponding solvates.

Very special preference is given to compounds of the general formula Ib,

in which

-   D stands for N or CH;-   R¹ stands for H; F; Cl; Br or I;-   R² stands for H; F; Cl; Br; I; methyl; —OH; —NH₂ or —OR¹⁶;-   R³ stands for H; F; Cl; Br; I; —NO₂; —OH; —NH₂; —NH—C(═O)—R¹³,    —OR¹⁶; SR¹⁷; —S(═O)—NR²²R²³ or —S(═O)—R²⁷;-   R⁴ stands for H; F; Cl; Br; I; methyl, —OH; —NH₂ or —OR¹⁶;-   R⁵ stands for H; F; Cl; Br; or I;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; tert-butyl; or —C(CH₃)₂(CH₂OH);-   R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently stand for a    radical selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl, and ethenyl;-   R⁴³ stands for a radical selected from the group consisting of    methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl;-    or for a radical selected from the group consisting of cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which    can be optionally substituted by 1, 2, 3, 4, or 5 substituents    independently selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and    n-pentyl;    in each case optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers, or the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or in each case in the form of corresponding    salts, or in each case in the form of corresponding solvates.

Preference is given to compounds of the general formula Ic,

in which

-   D stands for N or CH;-   R¹ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R² stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R³ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R⁴ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R⁵ stands for H; F; Cl; Br; I; —NO₂; —CF₃; —CN; —NH₂; —OH;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—NR²²R²³; —S(═O)₂—R²⁷, or for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and    tert-butyl;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; tert-butyl; or —C(CH₃)₂(CH₂OH);-   R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently stand for a    radical selected from the group consisting of methyl, —CF₃, —CHF₂,    —CH₂F, ethyl, —CF₂—CH₃, —CH₂—CF₃, —C₂F₅, n-propyl, isopropyl,    n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl,    n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl,    (2,6)-dimethylhept-4-yl, 3-methylbutyl, n-hexyl,    (3,3)-dimethylbutyl, and ethenyl;-   R⁴⁰ and R⁴¹ each independently stand for a radical selected from the    group consisting of methyl, —CH₂—O—CH₃, ethyl, n-propyl, n-butyl,    sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl,    (3,3)-dimethylbutyl, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—C₂H₅, and    —CH₂—CH₂—CH₂—O—CH₃;-    or for a radical selected from the group consisting of    2,3-dihydro-1H-indenyl, cyclopropyl, oxetanyl, cyclobutyl,    cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl,    tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl,    piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl,    each of which can be optionally substituted by 1, 2, 3, 4, or 5    substituents independently selected from the group consisting of    methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,    tert-butyl, and n-pentyl;-   or-   R⁴⁰ and R⁴¹ form, together with the interconnecting nitrogen atom as    ring member, a radical selected from the group consisting of    3-azabicyclo[3.1.1]heptyl, 6-azaspiro[2.5]octyl,    3-acabicyclo[3.2.1]octyl, 6-azabicyclo[3.3.1]heptyl,    8-acabicyclo[3.2.1]octyl, 1-oxa-2,8-diazaspiro[4.5]dec-2-enyl,    azocanyl, isoindolyl, indolyl, (1,2,3,6)-tetrahydropyridinyl,    (4,5,6,7)-tetrahydroisoxazolo[5.4-c]pyridinyl, pyrrolidinyl,    piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl, and    thiomorpholinyl, of which the heterocycloaliphatic moiety can in    each case be unsubstituted or substituted by 1, 2, 3, 4, or 5    radicals R⁵⁷;-   R⁵⁷ stands for —NHR⁵³, —NR⁵⁹R⁶⁰, or for an alkyl radical selected    from the group consisting of —CF₃, —CH₂—CF₃, methyl, ethyl,    n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl;-   R⁵⁸, R⁵⁹, and R⁶⁰ each independently stand for —C(═O)—R⁶¹;-    for an alkyl radical selected from the group consisting of —CF₃,    —CH₂—CF₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl,    sec-butyl, and isobutyl;-    or for a radical selected from the group consisting of phenyl and    naphthyl, and each radical can be bonded via a —(CH₂)—, —(CH₂)₂— or    —(CH₂)₃ group and/or can each be unsubstituted or optionally    substituted by 1, 2, 3, 4, or 5 substituents independently selected    from the group consisting of F, Cl, Br, I, —CN, —CF₃, —O—CH₃,    —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, methyl, ethyl, n-propyl,    isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;-   and-   R⁶¹ stands for an alkyl radical selected from the group consisting    of —CF₃, —CH₂—CF₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl,    n-butyl, sec-butyl, and isobutyl;    in each case optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers, or the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or in each case in the form of corresponding    salts, or in each case in the form of corresponding solvates.

Special preference is given to compounds of the general formula Ic,

in which

-   D stands for N or CH;-   R¹ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷,-   R² stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷—S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R³ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R⁴ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R⁵ stands for H; F; Cl; Br; I; methyl, ethyl, —NO₂; —OH; —NH₂;    —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³ or —(S═O)—R²⁷;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; tert-butyl; or —C(CH₃)₂(CH₂OH);-   R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently stand for a    radical selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl, and ethenyl;-   R⁴⁰ and R⁴¹ form, together with the interconnecting nitrogen atom as    ring member, a radical selected from the group consisting of    pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and azepanyl,    of which the heterocycloaliphatic moiety can in each case be    unsubstituted or substituted by 1, 2, 3, 4, or 5 radicals R⁵⁷;-   and-   R⁵⁷ stands for an alkyl radical selected from the group consisting    of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl,    sec-butyl, and isobutyl;    in each case optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers, or the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or in each case in the form of corresponding    salts, or in each case in the form of corresponding solvates.

Very special preference is given to compounds of the general formula Ic,

in which

-   D stands for N or CH; R¹ stands for H; F; Cl; Br; or I;-   R¹ stands for H; F; Cl; Br or I;-   R² stands for H; F; Cl; Br; I; methyl; —OH; —NH₂ or —OR¹⁶;-   R³ stands for H; F; Cl; Br; I; —NO₂; —OH; —NH₂; —NH—C(═O)—R¹³,    —OR¹⁶; SR¹⁷; —S(═O)—NR²²R²³ or —S(═O)—R²⁷;-   R⁴ stands for H; F; Cl; Br; I; methyl, —OH; —NH₂ or —OR¹⁶;-   R⁵ stands for H; F; Cl; Br; or I;-   R⁸ stands for —SF₅; —O—CF₃; —CF₃; tert-butyl; or —C(CH₃)₂(CH₂OH);-   R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently stand for a    radical selected from the group consisting of methyl, ethyl,    n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,    n-pentyl and ethenyl;-   R⁴⁰ and R⁴¹ form, together with the interconnecting nitrogen atom as    ring member, a radical selected from the group consisting of    pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and azepanyl,    of which the heterocycloaliphatic moiety can in each case be    unsubstituted or substituted by 1, 2, 3, 4, or 5 radicals R⁵⁷;-   and-   R⁵⁷ stands for an alkyl radical selected from the group consisting    of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl,    sec-butyl, and isobutyl;    in each case optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers, or the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or in each case in the form of corresponding    salts, or in each case in the form of corresponding solvates.

Even more preference is given to compounds of the general formulas I,Ia, Ib, and Ic selected from the group consisting of

-   [1]    2-(4-Amino-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [2]    2-(3,5-Dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [3]    2-(4-Amino-3-bromo-5-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [4]    2-(3-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [5]    2-(2,4-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [6]    2-(2,6-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [7]    2-(2,5-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [8]    2-(4-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [9]    2-(4-Hydroxy-3-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [10]    2-(3,5-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [1,1]    2-(3,4-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [12]    2-(4-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [13]    2-(3-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [14]    2-(3,4-Diaminophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [15]    N-(2-Butoxy-6-tert-butylpyridin-3-ylmethyl)-2-(3,4-diamino-phenyl)-propionamide;-   [16]    N-((6-tert-Butyl-2-(4-methylpiperidin-1-yl)pyridin-3-yl)methyl)-2-(3,4-diaminophenyl)propanamide;-   [17]    N-((6-tert-Butyl-2-(cyclohexylthio)pyridin-3-yl)methyl)-2-(3,4-diaminophenyl)propanamide;-   [18]    2-(4-Acetamido-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [19]    2-(3,5-Dibromo-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [20]    2-(4-Amino-3,5-dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;-   [21]    2-(3-Brom-4-hydroxy-5-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [22]    2-(4-Amino-3,5-dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [23]    2-(3,5-Dibromo-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;-   [24]    2-(3-Amino-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide;    and-   [25]    2-(3,5-Dibromophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide;-   [26]    2-(4-Amino-3,5-difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [27]    2-(3-Fluoro-5-hydroxy-4-nitrophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [28]    2-(3-Chloro-4-(methylthio)phenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [29]    2-(3-Chloro-4-(methylsulfonyl)phenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [30]    2-(3-Fluoro-4-(methylthio)phenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [31]    2-(3-Fluoro-4-(methylsulfonyl)phenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [32]    2-(4-(N,N-Dimethylsulfamoyl)-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [33]    N-(2-Fluoro-4-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl)phenyl)acrylamide,-   [34]    N-(2-Fluoro-6-iodo-4-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methylamino)-1-oxopropan-2-yl)phenyl)acrylamide,-   [35]    2-(4-Methoxy-3,5-dimethylphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [36]    2-(3,5-Difluoro-4-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [37]    2-(4-Hydroxy-3,5-dimethylphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,-   [38]    2-(3,5-Difluoro-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide,    each optionally in the form of one of the pure stereoisomers    thereof, particularly enantiomers or diastereoisomers thereof, the    racemates thereof or in the form of a mixture of stereoisomers,    particularly the enantiomers and/or diastereoisomers, in an    arbitrary mixing ratio, or each in the form of corresponding salts,    or each in the form of corresponding solvates;

Furthermore, preference may be given to compounds of the invention ofthe general formulas I, Ia, Ib and Ic, which in the FLIPR assay usingCHO-K1 cells, which have been transfected with the human VR1 gene in aconcentration below 2000 nM, preferably below 1000 nM, more preferablybelow 300 nM, even more preferably below 100 nM, still more preferablybelow 75 nM, very preferably below 50 nM and most preferably below 10nM, cause a 50 percent displacement of capsaicin present in aconcentration of 100 nM. In the FLIPR assay, the Ca²⁺ influx isquantified with the aid of a Ca²⁺-sensitive dye (type Fluo-4, MolecularProbes Europe BV, Leiden, Netherlands) in a fluorescent imaging platereader (FLIPR, Molecular Devices, Sunnyvale, USA), as described below.

The invention further relates to a process for the production ofcompounds of the above general formula I, according to which at leastone compound of the general formula II,

in whichR⁸, U, T, V, and W have the aforementioned meanings, m stands for 0, 1,2, or 3, and R stands for hydrogen or for a linear or branched C₁₋₆alkyl radical, in a reaction medium, in the presence of at least onereducing agent, preferably in the presence of at least one reducingagent selected from the group consisting of sodium hydride, sodium,potassium hydride, lithium aluminum hydride, sodium tetrahydridoborate,and di(isobutyl)aluminum hydrideis converted to at least one compound of the general formula III,

in whichR⁸, U, T, V, and W have the meanings stated above and m stands for 0, 1,2, or 3, and this is optionally purified and/or isolated,and at least one compound of the general formula III is converted, in areaction medium in the presence of diphenylphosphorylazide or in thepresence of HN₃, to at least one compound of the general formula IV,

in whichR⁸, U, T, V, and W have the meanings stated above and m stands for 0, 1,2, or 3, and this is optionally purified and/or isolated,and at least one compound of the general formula IV is converted, in areaction medium in the presence of at least one reducing agent,preferably in the presence of at least one reducing agent selected fromthe group consisting of sodium hydride, potassium hydride, lithiumaluminum hydride, sodium tetrahydridoborate, and di(isobutyl)aluminumhydride,or in a reaction medium in the presence of a catalyst, preferably in thepresence of a catalyst based on platinum or palladium, more preferablyin the presence of palladium-on-charcoal, and in the presence ofhydrogen or in the presence of hydrazine,or in a reaction medium in the presence of triphenylphosphineto at least one compound of the general formula V,

in whichR⁸, U, T, V, and W have the meanings stated above and m stands for 0, 1,2, or 3, and this is optionally purified and/or isolated,or at least one compound of the general formula VI

in whichR⁸, U, T, V, and W have the meanings stated above and m stands for 0, 1,2, or 3, in a reaction medium is converted, in the presence of at leastone catalyst, preferably in the presence of at least one catalyst basedon palladium or platinum, more preferably in the presence ofpalladium-on-charcoal, under a blanket of hydrogen, optionally in thepresence of at least one acid, preferably in the presence ofhydrochloric acid, or in the presence of at least one reducing agentselected from the group consisting of BH₃ bullet S(CH₃)₂, lithiumaluminum hydride, and sodium tetrahydridoborate, optionally in thepresence of NiCl₂,to form at least one compound of the general formula V, optionally inthe form of a corresponding salt, preferably in the form of acorresponding hydrochloride, and this is optionally purified and/orisolated,and at least one compound of the general formula V is caused to reactwith at least one compound of the general formula VII,

in whichR¹, R², R³, R⁴, R⁵, R⁶, and R⁷ have the meanings stated above, in areaction medium, optionally in the presence of at least one suitablecoupling agent, optionally in the presence of at least one base,or with at least one compound of the general formula VIII,

in whichR¹, R², R³, R⁴, R⁵, R⁶, and R⁷ have the meanings stated above and LGstands for a leaving group, preferably for a chlorine radical or bromineatom, in a reaction medium, optionally in the presence of at least onebase, to form at least one compound of the general formula I,

in whichT, U, V, W, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸, have the meanings statedabove and n stands for 1, 2, 3, or 4, and this is optionally purifiedand/or isolated.

The invention further relates to a process for the production ofcompounds of the above general formula I, according to which at leastone compound of the general formula X,

in whichR⁸, U, T, V, and W have the meanings stated above, is caused to reactwith at least one compound of the general formula VIII,

in whichR¹, R², R³, R⁴, R⁵, R⁶, and R⁷, have the meanings stated above, in areaction medium, optionally in the presence of at least one suitablecoupling agent, optionally in the presence of at least one base,or with at least one compound of the general formula VIII,

in whichR¹, R², R³, R⁴, R⁵, R⁶, and R⁷ have the meanings stated above and LGstands for a leaving group, preferably for a chlorine radical or bromineatom, in a reaction medium, optionally in the presence of at least onebase,to form at least one compound of the general formula Im,

in whichT, U, V, W, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ have the meanings statedabove, and this is optionally purified and/or isolated.

The reaction of compounds of the above general formulas V or X withcarboxylic acids of the above general formula VII to form compounds ofthe above general formulas I or Im is carried out preferably in areaction medium selected from the group consisting of diethyl ether,tetrahydrofuran, acetonitrile, methanol, ethanol, (1,2)-dichloroethane,dimethylformamide, dichloromethane and appropriate mixtures thereof,optionally in the presence of at least one coupling agent, preferablyselected from the group consisting of1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), dicyclohexylcarbodiimide (DCC),N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI),diisoproylcarbodiimide, 1,1′-carbonyldiimidazole (CDI),N-[(dimethylamino)-1H-1,2,3-triazolo[4.5-b]pyridino-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), N-hydroxybenzotriazole (HOBT), and1-hydroxy-7-azabenzotriazole (HOAt), optionally in the presence of atleast one organic base, preferably selected from the group consisting oftriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine, anddiisopropylethylamine, preferably at temperatures ranging from −70° C.to 100° C. Alternatively, the reaction of compounds of the above generalformulas V or X with carboxylic derivatives of the above general formulaVIII, in which LG stands for a leaving group, preferably for a chlorineradical or bromine atom, to form compounds of the above general formulasIm is carried out in a reaction medium preferably selected from thegroup consisting of diethyl ether, tetrahydrofuran, acetonitrile,methanol, ethanol, dimethylformamide, dichloromethane and appropriatemixtures thereof, optionally in the presence of an organic or inorganicbase, preferably selected from the group consisting of triethylamine,dimethylaminopyridine, pyridine, and diisopropylamine, at temperaturesranging from −70° C. to 100° C.

The compounds of the above formulas II, III, IV, V, VI, VII, X and VIIIare all commercially available and can be obtained by methods known tothe person skilled in the art.

The synthesis of compounds of the general formula VII is described inthe paper “4-(Methylsulfonylamino)phenyl analogues as vanilloidantagonist showing excellent analgesic activity and the pharmaceuticalcompositions comprising the same” by J. W. Lee et al. [WO2005/003084-A1].

The appropriate sections of this reference are included herein byreference and are to be regarded as part of the disclosure.

The conversions described above can each be carried out under usualconditions well-known to the person skilled in the art, for example, inrespect of pressure or order of addition of the components. Optionally,the optimal procedure under the respective conditions can be determinedby the person skilled in the art using simple preliminary tests. Theintermediates and end products obtained by the aforementioned reactionscan in each case be isolated and/or purified by conventional methodsknown to the person skilled in the art, if desired and/or necessary.Suitable clean-up techniques are, for example, extraction processes andchromatographic processes such as column chromatography or preparativechromatography. All of the process steps described above and thepurification and/or isolation of intermediate or end products can becarried out partially or completely under a blanket of inert gas,preferably under a blanket of nitrogen.

The substituted compounds of the invention of the aforementioned generalformulas I, Ia, Ib and Ic, designated below simply as compounds of thegeneral formula I, and corresponding stereoisomers can be isolatedeither in the form of the free bases thereof, the free acids thereof orin the form of corresponding salts, particularly physiologicallyacceptable salts.

The free bases of the respective substituted compounds of the inventionof the aforementioned general formula I and corresponding stereoisomerscan, for example by reaction with an inorganic or organic acid,preferably with hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonicacid, formic acid, acetic acid, oxalic acid, succinic acid, tartaricacid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamicacid, or aspartic acid, be converted to the corresponding salts,preferably physiologically acceptable salts. The free bases of therespective substituted compounds of the aforementioned general formula Iand corresponding stereoisomers can be likewise caused to react with thefree acid or a salt of a sugar substitute, such as saccharin, cyclamate,or acesulfam, to form the corresponding physiologically acceptablesalts. Similarly, the free acids of the substituted compounds of theaforementioned general formula I and corresponding stereoisomers can becaused to react with of a suitable base to form the correspondingphysiologically acceptable salts. Mention may be made, for example, ofthe alkali-metal salts, alkaline earth metal salts, or ammonium salts[NH_(x)R_(4-x)]⁺ in which x is equal to 0, 1, 2, 3, or 4, and R standsfor a linear or branched C₁₋₄ alkyl radical.

The substituted compounds of the invention designated by theaforementioned general formula I and corresponding stereoisomers canoptionally, like the corresponding acids, the corresponding bases orsalts of these compounds, be obtained in the form of the solvatesthereof, preferably in the form of the hydrates thereof, by conventionalmethods known to the person skilled in the art.

If the substituted compounds of the invention designated by theaforementioned general formula I are obtained, following productionthereof, in the form of a mixture of the stereoisomers thereof,preferably in the form of the racemates thereof or other mixtures of thevarious enantiomers and/or diastereoisomers thereof, these compounds canbe separated and, if desired, isolated by methods known to the personskilled in the art.

Examples of suitable isolation methods include chromatographicseparation methods, particularly liquid-chromatographic methods carriedout under standard pressure or at elevated pressure, preferably MPLC andHPLC methods, and also methods of fractional crystallization. Inparticular, individual enantiomers can be separated from each other,e.g., diastereoisomeric salts formed by means of HPLC on chiralstationary phase or by means of crystallization with chiral acids, say,(+)-tartaric acid, (−)-tartaric acid, or (+)-10-camphorsulfonic acid.

The substituted compounds of the invention designated by theaforementioned general formula I and corresponding stereoisomers and ineach case the corresponding acids, bases, salts, and solvates aretoxicologically safe and are therefore suitable for use aspharmaceutically active substances in medicinal drugs.

The invention therefore further relates to a medicinal drug containingat least one compound of the invention of the above general formula I,each optionally in the form of one of the pure stereoisomers thereof,particularly enantiomers or diastereoisomers thereof, the racematesthereof or in the form of a mixture of stereoisomers, particularly theenantiomers and/or diastereoisomers, in an arbitrary mixing ratio, oreach in the form of a corresponding salt, or each in the form of acorresponding solvate, and optionally one or more pharmaceuticallycompatible adjuvants.

These medicinal drugs of the inventions are particularly suitable forvanilloid receptor 1-(VR1/TRPV1) regulation, preferably vanilloidreceptor 1-(VR1/TRPV1) inhibition and/or vanilloid receptor1-(VR1/TRPV1) stimulation.

In another preferred embodiment, the medicinal drugs of the inventionare suitable for prophylaxis and/or treatment of disorders or diseasesthat are at least partially mediated by vanilloid receptors 1.

Preferably, the medicinal drug of the invention is suitable fortreatment and/or prophylaxis of one or more disorders selected from thegroup consisting of pain selected from the group consisting of acutepain, chronic pain, neuropathic pain and visceral pain; arthralgia;hyperalgesia; allodynia; causalgia; migraine; states of depression;nervous disorders; neurotraumas; neurodegenerative disorders, preferablyselected from the group consisting of multiple sclerosis, MorbusAlzheimer, Morbus Parkinson, and Morbus Huntington; cognitivedysfunctions, preferably cognitive deficiency states, more preferablymemory defects; epilepsy; respiratory tract diseases, preferablyselected from the group consisting of asthma, bronchitis, and pneumonia;coughing; urinary incontinence; an overactive bladder (OAB); disordersand/or injuries of the gastrointestinal tract; duodenal ulcers; gastriculcers; colitis syndrome; apoplectic strokes; eye irritations; cutaneousirritations; neurotic skin conditions; allergic skin diseases;psiorasis; vitiligo; Herpes simplex; inflammations, preferablyinflammation of the intestine, the eyes, the bladder, the skin, or thenasal mucosa; diarrhea; pruritus; osteoporosis; arthritis;osteo-arthritis; rheumatic disorders; food intake disorders, preferablyselected from the group consisting of bulimia, cachexia, anorexia, andobesity; medicine addiction; medicine abuse; withdrawal phenomenafollowing medicine addiction; tolerance development to pharmaceuticals,particularly to natural or synthetic opioids; drug addiction; drugabuse; withdrawal phenomena following drug addiction; alcohol addiction;alcohol abuse and withdrawal phenomena following alcohol addiction; fordiuresis; for antinatriuresis; for affection of the cardiovascularsystem; for vigilance enhancement; for treatment of wounds and/orburning; for treatment of severed nerves; for libido enhancement; formodulation of movement activity; for anxiolysis; for local anesthesiaand/or for inhibition of undesirable side effects, preferably selectedfrom the group consisting of hyperthermia, hypertension, and bronchialconstriction, as caused by administration of vanilloid receptor 1(VR1/TRPV1 receptor) agonists, preferably selected from the groupconsisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665,SDZ-249482, nuvanil, and capsavanil.

The medicinal drug of the invention is more preferably suitable fortreatment and/or prophylaxis of one or more disorders selected from thegroup consisting of pain, preferably pain selected from the groupconsisting of acute pain, chronic pain, neuropathic pain, and visceralpain; arthralgia; migraine; states of depression; neurodegenerativedisorders, preferably selected from the group consisting of multiplesclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington;cognitive dysfunctions, preferably cognitive deficiency states, morepreferably memory defects; inflammation, preferably inflammation of theintestine, the eyes, the bladder, the skin or the nasal mucosa; urinaryincontinence; an overactive bladder (OAB); medicine addiction; medicineabuse; withdrawal phenomena following medicine addiction; tolerancedevelopment to pharmaceuticals, preferably tolerance development tonatural or synthetic opioids; drug addiction; drug abuse; withdrawalphenomena following drug addiction; alcohol addiction; alcohol abuse andwithdrawal phenomena following alcohol addiction.

The medicinal drug of the invention is most preferably suitable fortreatment and/or prophylaxis of pain, preferably pain selected from thegroup consisting of acute pain, chronic pain, neuropathic pain, andvisceral pain, and/or urinary incontinence.

The invention further relates to the use of at least one compound of theinvention and optionally one or more pharmaceutically compatibleadjuvants for the production of a medicinal drug for vanilloid receptor1-(VR1/TRPV1) regulation, preferably vanilloid receptor 1-(VR1/TRPV1)inhibition and/or vanilloid receptor 1-(VR1/TRPV1) stimulation.

Preference is given to the use of at least one substituted compound ofthe invention and optionally one or more pharmaceutically compatibleadjuvants for the production of a medicinal drug for the prophylaxisand/or treatment of disorders or diseases which are at least partiallymediated by vanilloid receptors 1.

Particular preference is given to the use of at least one compound ofthe invention and optionally one or more pharmaceutically compatibleadjuvants for the production of a medicinal drug for treatment and/orprophylaxis of one or more disorders selected from the group consistingof pain, preferably of pain selected from the group consisting of acutepain, chronic pain, neuropathic pain, visceral pain, and arthralgia.Particular preference is given to the use at least one compound of theinvention and optionally one or more pharmaceutically compatibleadjuvants for the production of a medicinal drug for treatment and/orprophylaxis of one or more disorders selected from the group consistingof hyperalgesia; allodynia; causalgia; migraine; states of depression;nervous disorders; neurotraumas; neurodegenerative disorders, preferablyselected from the group consisting of multiple sclerosis, MorbusAlzheimer, Morbus Parkinson, and Morbus Huntington; cognitivedysfunctions, preferably cognitive deficiency states, more preferablymemory defects; epilepsy; respiratory tract diseases, preferablyselected from the group consisting of asthma, bronchitis, and pneumonia;coughing; urinary incontinence; an overactive bladder (OAB); disordersand/or injuries of the gastrointestinal tract; duodenal ulcers; gastriculcers; colitis syndrome; apoplectic strokes; eye irritations; cutaneousirritations; neurotic skin conditions; allergic skin diseases;psiorasis; vitiligo; Herpes simplex; inflammation, preferablyinflammation of the intestine, the eyes, the bladder, the skin, or thenasal mucosa; diarrhea; pruritus; osteoporosis; arthritis;osteo-arthritis; rheumatic disorders; food intake disorders, preferablyselected from the group consisting of bulimia, cachexia, anorexia, andobesity; medicine addiction; medicine abuse; withdrawal phenomenafollowing medicine addiction; tolerance development to pharmaceuticals,preferably to natural or synthetic opioids; drug addiction; drug abuse;withdrawal phenomena following drug addiction; alcohol addiction;alcohol abuse and withdrawal phenomena following alcohol addiction; fordiuresis; for antinatriuresis; for affection of the cardiovascularsystem; for vigilance enhancement; for treatment of wounds and/orburning; for treatment of severed nerves; for libido enhancement; formodulation of movement activity; for anxiolysis; for local anesthesiaand/or for inhibition of undesirable side effects, preferably selectedfrom the group consisting of hyperthermia, hypertension, and bronchialconstriction, as caused by administration of vanilloid receptor 1(VR1/TRPV1 receptor) agonists, preferably selected from the groupconsisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665,SDZ-249482, nuvanil, and capsavanil.

Very high preference is given to the use of at least one substitutedcompound of the invention and optionally one or more pharmaceuticallycompatible adjuvants for the production of a medicinal drug fortreatment and/or prophylaxis of one or more disorders selected from thegroup consisting of pain, preferably pain selected from the groupconsisting of acute pain, chronic pain, neuropathic pain, and visceralpain; arthralgia; migraine; states of depression; neurodegenerativedisorders, preferably selected from the group consisting of multiplesclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington;cognitive dysfunctions, preferably cognitive deficiency states, morepreferably memory defects; inflammation, preferably inflammation of theintestine, the eyes, the bladder, the skin, or the nasal mucosa; urinaryincontinence; an overactive bladder (OAB); medicine addiction; medicineabuse; withdrawal phenomena following medicine addiction; tolerancedevelopment to pharmaceuticals, preferably tolerance development tonatural or synthetic opioids; drug addiction; drug abuse; withdrawalphenomena following drug addiction; alcohol addiction; alcohol abuse andwithdrawal phenomena following alcohol addiction. Even more preferenceis given to the use of at least one substituted compound of theinvention and optionally one or more pharmaceutically compatibleadjuvants for the production of a medicinal drug for treatment and/orprophylaxis of pain, preferably selected from the group consisting ofacute pain, chronic pain, neuropathic pain, and visceral pain, and/orurinary incontinence.

The medicinal drug of the invention is suitable for administration toadults and children including infants and babies.

The medicinal drug of the invention can exist as a liquid, semisolid, orsolid pharmaceutical dosage form, for example, in the form of injectionfluids, drops, juices, syrups, sprays, suspensions, tablets, patches,capsules, plasters, suppositories, ointments, creams, lotions, gels,emulsions, or aerosols, or in a multiparticular form, for example, inthe form of pellets or granules, optionally compressed to tablets,filled into in capsules, or suspended in a liquid, and can beadministered as such.

In addition to at least one substituted compound of the above generalformula I, optionally in the form of a pure stereoisomer thereof,particularly an enantiomer or diastereoisomer, the racemate thereof orin the form of mixtures of the stereoisomers, particularly theenantiomers or diastereoisomers, in an arbitrary mixing ratio, oroptionally in the form of a corresponding salt or each in the form of acorresponding solvate, the medicinal drug of the invention usuallycontains further physiologically acceptable pharmaceutical adjuvants,which, for example, can be selected from the group consisting ofvehicles, fillers, solvents, diluents, surfactants, dyes, preservatives,blasting agents, slip agents, lubricants, flavors, and binding agents.

The selection of the physiologically acceptable adjuvants and the amountthereof to be used depends on whether the medicinal drug is to beapplied orally, subcutaneously, parenterally, intravenously,intraperitoneally, intradermally, intramuscularly, intranasally,buccally, rectally or locally, e.g., to infected parts of the skin, themucous membrane, or the eyes. Preparations suitable for oraladministration are preferably in the form of tablets, dragees, capsules,granules, pellets, drops, juices, and syrups, and preparations suitablefor parenteral, topical and inhalative administration are solutions,suspensions, readily reconstitutable dry preparations, and sprays. Thesubstituted compounds of the invention used in the medicinal drug of theinvention in a depot in dissolved form or in a plaster, optionally withthe addition of skin penetration enhancing agents, are suitablepercutane administration forms. Formulations for oral or percutaneapplication may be such as to effect delayed release of the respectivesubstituted compound of the invention. The production of the medicinaldrug of the invention is effected by conventional means, devices,methods, and processes, as are known in the prior art, such as aredescribed, for example, in “Remington's Pharmaceutical Sciences”, EditorA. R. Gennaro, 17th Edition, Mack Publishing Company, Easton, Pa., 1985,particularly in Section 8, Chapters 76 to 93. The correspondingdescription is incorporated herein by reference and is to be regarded aspart of the disclosure. The amount of the respective substitutedcompounds of the invention of the above general formula I to beadministered to the patients can vary and is dependent, for example, onthe weight or age of the patient and also on the method ofadministration, the indication, and the severity of the disorder.Usually from 0.001 to 100 mg/kg, preferably from 0.05 to 75 mg/kg andmore preferably from 0.05 to 50 mg/kg, of body weight of the patient ofat least one such compound of the invention are administered.

Pharmacological Methods:

I. Functional Investigation on the Vanilloid Receptor 1 (VR1/TRPV1Receptor)

The agonistic or antagonistic action of the substances to beinvestigated on the vanilloid receptor 1 (VR1/TRPV1) of the species ratcan be determined using the following assay. According to this assay,the Ca²⁺ influx through the receptor channel is quantified with the aidof a Ca²⁺-sensitive dye (Type Fluo-4, Molecular Probes Europe BV, LeidenNetherlands) in a fluorescent imaging plate reader (FLIPR, MolecularDevices, Sunnyvale, USA).

Method:

Complete medium: 50 mL of HAMS F12 Nutrient Mixture (Gibco InvitrogenGmbH, Karlsruhe, Germany) with

10% by volume of FCS (fetal calf serum, Gibco Invitrogen GmbH,Karlsruhe, Germany, heat-inactivated);

2 mM of L-glutamine (Sigma, Munich, Germany);

1% by weight of AA solution (antibiotics/antimycotics solution, PAA,Pasching, Austria)

and 25 ng/mL of Medium NGF (2.5 S, Gibco Invitrogen GmbH, Karlsruhe,Germany) Cell culture plate: Poly-D-lysine-coated, black 96-well plateswith a clear bottom (96-well black/clear plate, BD Biosciences,Heidelberg, Germany) are additionally coated with laminin (GibcoInvitrogen GmbH, Karlsruhe, Germany) by diluting laminin to aconcentration of 100 μg/mL with PBS (Ca—Mg-free PBS, Gibco InvitrogenGmbH, Karlsruhe, Germany). Aliquots having a concentration of 100 μg/mLof laminin are taken and stored at −20° C. The aliquots are diluted withPBS in the ratio 1:10 to 10 μg/mL of laminin and in each case 50 μL ofthe solution is pipeted into a well of the cell culture plate. The cellculture plates are incubated at 37° C. for at least two hours, thesupernatant solution is aspirated and the wells are in each case washedtwice with PBS. The coated cell culture plates are stored withsupernatant PBS and this is removed only directly before the addition ofthe cells.Preparation of the Cells:

The vertebral column is removed from decapitated rats and this is laiddirectly in a cold, i.e. ice bath-surrounded, HBSS buffer (Hank'sbuffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) and1% by volume of an M solution (antibiotics/antimycotics solution, PAA,Pasching, Austria) is added. The vertebral column is cut in two,longitudinally, and the vertebral canal is removed together withfascias. Subsequently, the dorsal root ganglia (DRGs) are removed and inturn stored in cold HBSS buffer to which 1% by volume of an AA solutionhas been added. The DRGs completely freed from blood residues and spinalnerves are in each case transferred to 500 μL of cold collagenase Type 2(PAA, Pasching, Austria) and incubated at 37° C. for 35 minutes. Afterthe addition of 2.5% by volume of trypsin (PAA, Pasching, Austria), thepreparation is incubated at 37° C. for a further 10 minutes. Oncompletion of incubation, the enzyme solution is carefully pipeted offand 500 μL of complete medium are added to the DRGs in each case. TheDRGs are in each case repeatedly suspended, drawn through No. 1, No. 12,and No. 16 needles by means of a syringe and transferred to 50 mL Falcontubes and these are filled to 15 mL with complete medium. The contentsof each Falcon tube are in each case filtered through a 70 μm Falconfilter insert and centrifuged at 1200 rpm and RT for 10 minutes. Theresulting pellet is in each case taken up in 250 μL of complete mediumand the cell count is determined.

The number of cells in the suspension is adjusted to 3×10⁵ per mL and ineach case 150 μL of this suspension are added to a well of the cellculture plates coated as described above. The plates are allowed tostand at 37° C., 5% by volume of CO₂ and 95% relative humidity for twoto three days in an incubator.

Subsequently, the cells are loaded with 2 μM of Fluo-4 and 0.01% byvolume of Pluronic F127 (Molecular Probes Europe BV, Leiden Netherlands)in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH,Karlsruhe, Germany) at 37° C. for 30 min, washed 3 times with HBSSbuffer and, after a further incubation of 15 minutes at RT, employed inthe FLIPR assay for Ca²⁺ measurement. The Ca²⁺— dependent fluorescenceis measured before and after addition of substances (λex=488 nm, λem=540nm). Quantification is carried out by measuring the highest fluorescenceintensity (FC, fluorescence counts) over time.

FLIPR Assay:

The FLIPR protocol consists of two substance additions. Initially, thecompounds to be tested (10 μM) are pipeted onto the cells and the Ca²⁺influx is compared with the control (capsaicin 10 μM). Information isgained therefrom in percentage activation relative to the Ca²⁺ signalafter addition of 10 μM of capsaicin (CP). After incubation for 5minutes, 100 nM of capsaicin are applied and the influx of Ca²⁺ islikewise determined.

Desensitizing agonists and antagonists lead to suppression of the Ca²⁺influx. The percentage inhibition is calculated in comparison with themaximum inhibition achieved with 10 μM of capsaicin. Conversion usingthe Cheng Prusoff equation gave K_(i) values for the test substances(Cheng, Prusoff; Bioch. Pharmacol. 22, 3099-3108, 1973).

II. Functional Investigations on the Vanilloid Receptor (VR1)

The agonistic or antagonistic action of the substances to be examined onthe vanilloid receptor (VR1) can alternatively be determined by thefollowing assay. According to this assay the Ca²⁺ influx through thecanal is quantified with the aid of a Ca²⁺-sensitive dye (type Fluo-4,Molecular Probes, Europe BV, Leiden, Netherlands) in a fluorescentimaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).

Method:

Chinese hamster ovary cells (CHO-K1 cells, European Collection of CellCultures (ECACC) UK) are stably transfected with the VR1 gene. Forcarrying out functional investigations, these cells are plated onpoly-D-lysine-coated, black 96-well plates with a clear bottom (BDBiosciences, Heidelberg, Germany) in a density of 25,000 cells/well. Thecells are incubated overnight at 37° C. and 5% CO₂ in a culture medium(Nutrient Mixture ‘am’s F12, 10% by volume of FCS (fetal calf serum), 18μg/mL of L-proline). On the following day the cells are incubated withFluo-4 (Fluo-4 2 μM, Pluronic F127 0.01 by volume, Molecular Probes inHBSS (Hank's buffered saline solution), Gibco Invitrogen GmbH,Karlsruhe, Germany) for 30 minutes at 37° C. The plates are then washed3 times with HBSS buffer and, after another incubation over a period of15 minutes at RT, are used in the FLIPR for Ca²⁺ measurement. TheCa²⁺-dependent fluorescence is measured prior to and following theaddition of the substances being examined (wavelength λex=488 nm,λem=540 nm). Quantification is carried out by measuring the highestfluorescence intensity (PC, fluorescence counts) over time.

FLIPR Assay:

The FLIPR protocol consists of two substance additions. First of all,the substances to be tested (10 μM) are pipeted onto the cells and theCa²⁺ influx is compared with the control (capsaicin 10 μM) (percentageactivation based on the Ca²⁺ signal following addition of 10 μM ofcapsaicin). Following incubation over a period of 5 minutes 100 nM ofcapsaicin are applied and the influx of Ca²⁺ is likewise determined.

Desensitizing agonists and antagonists lead to a suppression of the Ca²⁺influx. The percentage inhibition compared with the maximum inhibitionachieved with 10 μM of capsaicin is calculated.

Based on the percentage displacement effected by differentconcentrations of the compounds of the general formula I to be tested,IC₅₀ inhibition concentrations that cause 50 percent displacement ofcapsaicin are calculated. Conversion using the Cheng Prusoff equationgave K_(i) values for the test substances (Cheng, Prusoff; Bioch.Pharmacol. 22, 3099-3108, 1973).

III. Formalin Test on Mice

The investigation for the determination of the antinociceptive action ofthe compounds of the invention is carried out in the formalin test onmale mice (NMRI, of 20 to 30 g body weight, Iffa, Credo, Belgium).

In the formalin test, the first (early) phase (0 to 15 minutes after theformalin injection) and the second (late) phase (15 to 60 minutes afterthe formalin injection) are distinguished according to D. Dubuisson etal., Pain 1977, 4, 161-174. The early phase, as a direct reaction to theformalin injection, is a model of acute pain, whereas the late phase isregarded as a model of persistent (chronic) pain (T. J. Coderre et al.,Pain 1993, 52, 259-285). The appropriate literature references areincorporated herein by reference and are to be regarded as part of thedisclosure.

The compounds of the invention are examined in the second phase of theformalin test, in order to obtain information concerning a substance'saction on chronic/inflammatory pain.

The point in time of administration of the compounds of the inventionbefore the formalin injection is selected according to the method ofadministration of the compounds of the invention. Intravenousadministration of 10 mg/kg of body weight of the test substance iscarried out 5 minutes before the formalin injection. This is carried outby a single subcutaneous formalin injection (20 μL, 1% strength aqueoussolution) into the dorsal side of the right hind paw so that in the caseof free-moving experimental animals a nociceptive reaction is inducedwhich is manifested by marked licking and biting of the relevant paw.

The nociceptive behavior is then continuously registered during aninvestigation period of three minutes in the second (late) phase of theformalin test (21 to 24 minutes after the formalin injection) byobservation of the animals. Quantification of the pain behavior iscarried out by summating the seconds during which the animals showlicking and biting of the relevant paw during the investigation period.In each case, comparison is carried out with control animals, whichreceive, instead of the compounds of the invention, a vehicle (0.9%strength aqueous sodium chloride solution) prior to formalinadministration. Based on the quantification of the pain behavior, thesubstance's action in the formalin test is determined as the degree ofchange compared with the corresponding control.

Following injection of the substances having an antinociceptive actionin the formalin test, the aforementioned behavioral patterns of theanimals, i.e. licking and biting, decrease or cease.

IV. Test for Analgesic Effectiveness in the Writhing Test

Investigation of the compounds of the general formula I of the inventionfor analgetic effectiveness was carried out based onphenylquinone-induced writhing in mice, modified after I. C. Hendershotand J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240. Thecorresponding literature reference is incorporated herein by referenceand is to be regarded as part of the disclosure.

For this purpose, male NMRI mice having a weight of from 25 to 30 g wereused. Groups of 10 animals per dose of the test compound received byintraperitoneal administration, 10 minutes after intravenousadministration of the compound under test, 0.3 mL/mouse of a 0.02%strength aqueous solution of phenylquinone (phenylbenzoquinone, marketedby Sigma, Deisenhofen, Germany and produced by adding to the solution 5%by weight of ethanol and storing it in a water bath at 45° C.). Theanimals were placed individually in observation cages. With the aid of apushbutton counter, the number of pain-induced stretching movements(so-called writhing reactions—straightening of the body with stretchingof the rear extremities) was counted over a period of from 5 to 20minutes following the administration of the phenylquinone. The controlwas provided by animals receiving only physiological saline. All of thecompounds were tested using the standard dosage of 10 mg/kg.

V. Hypothermia Assay in Mice

Description of the Method:

The hypothermia assay was carried out on male NMRI mice (weight 25-35gram, Zuechter IFFA CREDO, Brussels, Belgium). The animals were keptunder standardized conditions: light/dark rhythm (from 6:00 to 18:00hours light phase; from 18:00 to 6:00 hours dark phase), RT 19-22° C.,relative air humidity 35-70%, 15 air changes per hour, air movement <0.2m/sec. The animals received standard feed (ssniff R/M−Haltung, ssniffSpezialdiaeten GmbH, Soest, Germany) and tap water. Water and feed werewithdrawn during the experiment. All animals were used only once duringthe experiment. The animals had an acclimatization period of at least 5days.

Acute administration of capsaicin (VR-1 agonist) leads to a drop in thecore temperature of the body in rats and mice due to stimulation of heatsensors. Only specifically effective VR-1 receptor antagonists canantagonize the capsaicin-induced hypothermia. By contrast, hypothermiainduced by morphine is not antagonized by VR-1 antagonists. This modelis therefore suitable for identifying substances with VR-1 antagonisticproperties via their effect on body temperature.

Measurement of the core temperature is carried out using a digitalthermometer (Thermalert TH-5, physitemp, Clifton N.J., USA). The sensingelement is inserted into the rectum of the animals.

To give an individual basic value for each animal, the body temperatureis measured twice at an interval of approximately half an hour. Onegroup of animals (n=6 to 10) then receives an intraperitoneal (i.p.)application of capsaicin 3 mg/kg and vehicle (control group). Anothergroup of animals receives the substance to be tested (i.v. or p.o.) andadditionally capsaicin (3 mg/kg) i.p. The administration of the testsubstance is carried out i.v. 10 min, or p.o 15 minutes, prior tocapsaicin. The body temperature is then measured 7.5/15 and 30 minfollowing capsaicin (i.v.+i.p.) or 15/30/60/90/120 min (p.o.+i.p.)following capsaicin. In addition, one group of animals is treated withthe test substance only and one group with vehicle only. The evaluationor representation of the measured values as mean+/−SEM of the absolutevalues is presented as a graphical representation. The antagonisticaction is calculated as the percentage reduction of thecapsaicin-induced hypothermia.

VI. Neuropathic Pain in Mice

The investigation on effectiveness on neuropathic pain was examinedusing the Bennett Model (chronic constriction injury; Bennett und Xie,1988, Pain 33:87-107). Three loose ligatures are tied around the rightischiadic nerve of Ketavet/Rompun-anesthetized NMRI mice weighing 16-18g. The animals develop hypersensitivity of the nervate paw caused by thedamaged nerve, which hypersensitivity is quantified, following arecovery phase of one week, over a period of approximately three weeksby means of a cold metal plate (temperature 4° C.) (cold allodynia). Theanimals are observed on this plate over a period of 2 min, and thewithdrawal reactions of the damaged paw are counted. Based on thepre-value prior to administration of substance, the substance's actionover a certain period of time is determined at various points in time(e.g., 15, 30, 45, or 60 min following administration) and the resultantarea under the curve (AUC) and/or the inhibition of cold allodynia atthe individual measuring points was/were expressed as percentage actionrelative to the vehicle control (AUC) or to the starting value(individual measuring points). The group size is n=10, the significanceof an anti-allodynic action (*=p<0.05) is determined with the aid of ananalysis of variance with repeated measures and Bonferroni post hocanalysis.

The invention is described below with reference to some examples. Theseexplanations are by way of example only and do not restrict the generalinventive concept.

EXAMPLES

The yields of the compounds produced were not optimized. Alltemperatures are uncorrected. The statement “equivalents” denotes molequivalents, “RT” room temperature, “M” and “N” are concentrations inmol/L, “aq.” aqueous, “sat.” saturated, “soln. solution, and otherabbreviations are:

AvOH acetic acid DCM dichloromethane DMF N,N-dimethylformamide EDClN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride EA ethylacetate H₂O water HOBt N-hydroxybenzotriazole MeOH methanol THFtetrahydrofuran

The chemicals and solvents used were obtained commercially from theusual suppliers (Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster,Maybridge, Merck, Sigma, TCI, Oakwood etc.) or synthesized by usualmethods known to the person skilled in the art.

The stationary phase used for column chromatography was silica gel 60(0.0-0-0.063 mm) supplied by E. Merck, Darmstadt.

The thin-layer chromatographic analyses were carried out using preformedHPTLC plates, Silica Gel 60 F 254, supplied by E. Merck, Darmstadt.

The mixing ratios of solvents, mobile solvents, or for chromatographicanalyses are always stated in vol/vol.

Chemical analysis was carried out by mass spectroscopy and NMR.

1. General Instructions for Preparing Amines of the General Formula V-A

Preparation of Amines of the General Formula V-A is Carried Out asIllustrated by the following scheme 1.

Stage 1: Preparation of Nitrites of the General Formula VI-BMethod A:

Compounds of the general formula VI-A (1 equivalent), in which R⁸, U, T,and V have the meanings stated above and m stands for 0, 1, 2, or 3, arestirred with an amine of the general formula HNR⁴⁰R⁴¹ (6 equivalents)over a period of 48 hours at RT. To the reaction mixture there is added1N hydrochloric acid, and the mixture is extracted with EA a number oftimes. The aqueous phase is saturated with NaCl and then again extractedwith EA. The combined organic phases are washed with 1N hydrochloricacid and with sat. aq. NaCl soln., dried over MgSO₄, and the solvent isremoved in vacuo. The following compound was obtained by method A:

6′-tert-Butyl-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-carbonitrile

¹H-NMR (CDCl₃) δ 7.65 (d, 1H, J=7.9 Hz, Ar), 6.70 (d, 1H, J=8.0 Hz, Ar),4.45 (m, 2H, piperidine), 2.98 (m, 2H, piperidine), 1.75-1.24 (m, 5H,piperidine), 1.29 (s, 9H, C(CH₃)₃), 0.98 (d, 3H, J=5.9 Hz, CHCH₃)

IR 2956, 2213, 1583, 1550, 1452, 1230, 965 cm⁻¹

Method B:

Compounds of the general formula VI-A (1 equivalent), in which R⁸, U, T,and V have the meanings stated above and m stands for 0, 1, 2, or 3, arestirred with an amine of the general formula HNR⁴⁰R⁴¹ (2 equivalents)and DBU [1.8-diaza-bicyclo[5.4.0]undec-7-ene] (2 equivalents) inacetonitrile (7 mL per mmol of the compound of formula VI-A) over aperiod of 12 hours at RT. The reaction mixture is extracted with EA anumber of times. The combined organic phases are washed with sat. aq.NaCl solution, dried over MgSO₄, and the solvent is removed in vacuo.The residue is purified in each case by column chromatography (SiO₂,various mixtures of hexane/EA). The following compound was produced bymethod B.

6-(Trifluoromethyl)-2-(4-methylpiperidin-1-yl)pyridine-3-carbonitrile

¹H NMR (300 M Hz, CDCl₃) δ 7.87 (d, 1 h, J=7.8 Hz), 6.95 (d, 1 h, J=7.8Hz), 4.53 (m, 2H), 3.05 (m, 2H), 1.78 (m, 2H), 1.64 (m, 1H), 1.29 (m,2H), 1.00 (d, 3H, J=6.6 Hz); IR (PUR) 2926, 2852, 2218, 1590, 1497,1456, 1324, 1237, 1186, 1147, 1082, of 963 cm⁻¹; MS (FAB) m/z 270 (M+H)

Step 2:

Method 1

Compounds of the general formula VI-B (5 mmol), in which R⁸, R⁴⁰, R⁴¹,U, T, and V have the meanings stated above and m stands for 0, 1, 2, or3, palladium-on-charcoal (10%, 500 mg) and conc. hydrochloric acid (3mL) are dissolved in MeOH (30 mL) and exposed to a hydrogen atmosphereover a period of 6 hours at RT. The reaction mixture is filtered overCelite and the filtrate is concentrated in vacuo. The residue ispurified by means of flash chromatography (SiO₂, EA).

Method 2:

Compounds of the general formula VI-B (2 mmol), in which R⁸, R⁴⁰, R⁴¹,U, T, and V have the meanings stated above and m stands for 0, 1, 2, or3, are dissolved in THF (10 mL, 10 mL), and BH₃.S(CH₃)_(2 [)2.0 M inTHF, 3 mL, 3 equivalents] is added. The reaction mixture is heated underreflux over a period of 8 hours, aq. HCl (2N) is added and the reactionmixture is again heated under reflux for 30 minutes. Aq. sodiumhydroxide solution (2N) is added to the reaction mixture, and themixture is washed with EA. The combined organic phases are washed withsat. aq. NaCl solution and dried over magnesium sulfate. The solvent isremoved in vacuo and the residue purified by column chromatography(SiO₂, various mixtures of dichloromethane and MeOH as mobile solvent).The following compounds were obtained by method 2.

(6-(Trifluoromethyl)-2-(4-methylpiperidin-1-yl)pyridin-3-yl)methanamine

¹H NMR (300 M Hz, CDCl₃) δ 7.89 (d, 1H, J=7.8 Hz), 7.33 (d, 1H, J=7.8Hz), 3.88 (s, 2H), 3.39 (m, 2H), 2.83 (m, 2H), 1.75 (m, 2H), 1.55 (m,1H), 1.38 (m, 2H), 1.00 (d, 3H, J=6.6 Hz); MS (FAB) m/z 274 (M+H)

C-(6′-tert-Butyl-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-methylamine

¹H-NMR (CDCl₃) δ 7.48 (d, 1H, J=7.7 Hz, Ar), 6.90 (d, 1H, J=7.7 Hz, Ar),3.82 (s, 2H, CH₂NH₂), 3.38 (m, 2H, piperidine), 2.81 (m, 2H,piperidine), 1.73-1.28 (m, 5H, piperidine), 1.31 (s, 9H, C(CH₃)₃), 0.98(d, 3H, J=6.4 Hz, CHCH₃)

IR 3363, 2954, 1571, 1451, 1400, 1372, 1234, 960 cm⁻¹

2. General Instructions for the Preparation of Amines of the GeneralFormula V-E

The preparation of amines of the general formula V-E is carried out asillustrated in the following scheme 2.

Step 1 Synthesis of2-(cyclohexylthio)-6-(trifluoromethyl)nicotinonitrile

1.3 Equivalents of NaH (4.9 g, 0.124 mol) were dissolved in 50 mL of DMFunder a blanket of nitrogen. Following the addition of 1.2 equivalentsof cyclohexanethiol (14.2 mL, 0.116 mol), the mixture was stirred at RTover a period of 1.5 h. The resulting suspension was cooled to 10° C.and added dropwise to 1 equivalent of2-chloro-6-(trifluoromethyl)nicotinonitrile (20 g, 0.096 mol) in 50 mLof DMF and stirred over a period of 2 h at RT. To the reaction mixturethere was added sat. aq. NH₄Cl soln. and the mixture was diluted with 1L of water and extracted with EA (3×200 mL). The combined organic phaseswere washed with sat. aq. NaCl solution, dried over MgSO₄ andconcentrated in vacuo. Column chromatographic purification (silica gel100-200 mesh, eluant: 2% EA in hexane) yielded 26 g (93.8%) of product.

¹H NMR (300 M Hz, CDCl₃) δ 7.94 (d, 1H, J=7.9 Hz), 7.34 (d, 1H, J=7.9Hz), 4.00 (m, 1H), 1.90-2.14 (m, 2H), 1.42-1.88 (m, 8H)

IR (neat) 2930, 2854, 2232, 1643, 1573, 1447, 1334, 1245, 1186, 1149,1107, 851 cm⁻¹

MS (FAB) m/z 287 (M+H)

Step 2 Synthesis of(2-(cyclohexylthio)-6-(trifluoromethyl)-pyridin-3-yl)methanaminedihydrochloride

The nitrile (26 g, 0.091 mol) was dissolved in 600 mL of THF under ablanket of nitrogen and cooled to 5° C. BH₃-dimethyl sulfide (13.78 g,0.182 mol) was added dropwise and the mixture was boiled under refluxover a period of 20 h. After cooling to 5° C., 100 mL of MeOH were addedto the reaction batch and the mixture was stirred at RT over a period of15 minutes. Di-tert-butyldicarbonate (29.7 g, 0.136 mol) was then addedand the mixture was stirred at RT for 30 min. Following the removal ofthe solvent in vacuo, the crude product was purified by columnchromatography (silica gel 100-200 mesh, eluant: 10% EA in hexane) and23.4 g (66%) of product were obtained. The crude product was dissolvedin 120 mL of sat. HCl/dioxane soln., and the solution was stirred at RTover a period of 6 h. Following the removal of the solvent in vacuo, thesolid matter was washed with 10% of EA in hexane (2×100 mL) and isolatedby filtration. Yield: 17 g (88.8%)

¹H NMR (DMSO-d₆, 400 M Hz): δ 8.8 (s, 2H), 8.05 (d, 1H), 7.76 (d, 1H),4.01 (s, 1H), 3.86-3.93 (m, 1H), 2.02-2.08 (m, 2H), 1.71-1.74 (m, 2H),1.40-1.60 (m, 6H).

3. General Instructions for the Preparation of Amines of the GeneralFormula V-B

The preparation of amines of the general formula V-B is carried out asillustrated in the following scheme 3.

Step 1 Preparation of Nitriles of the General Formula VI—C

Compounds of the general formula VI-A (1 equivalent), in which R⁸, U, T,and V have the meanings stated above and m stands for 0, 1, 2, or 3, arestirred with an alcohol of the general formula HO—R⁴² (3.5 equivalents)and DBU [1,8-diaza-bicyclo[5.4.0]undec-7-ene] (3.5 equivalents) inacetonitrile (7 mL per mmol of the compound of formula VI-A) over aperiod of 12 hours at RT. The reaction mixture is extracted with EA anumber of times. The combined organic phases are washed with sat. aq.NaCl soln. and dried over MgSO₄, and the solvent is removed in vacuo.The residue is purified in each case by column chromatography (SiO₂,various mixtures of hexane/EA).

Method 2:

Compounds of the general formula VI—C (2 mmol), in which R⁸, R⁴², U, T,and V have the meanings stated above and m stands for 0, 1, 2, or 3, aredissolved in THF (10 mL, 10 mL) and BH₃.S(CH₃)_(2 [)2.0 M in THF, 3 mL,3 equivalent] is added. The reaction mixture is heated under reflux overa period of 8 hours, aq. HCl (2N) is added and the reaction mixture isagain heated under reflux for 30 minutes. Aq. sodium hydroxide solution(2N) is added to the reaction mixture, and the mixture is washed withEA. The combined organic phases are washed with sat. aq. NaCl solutionand dried over magnesium sulfate. The solvent is removed in vacuo andthe residue is purified by column chromatography (SiO₂, various mixturesof dichloromethane and methanol as mobile solvent).

Method 3:

Compounds of the general formula VI—C (1.5 mmol), in which R⁸, R⁴², U,T, and V have the meanings stated above and m stands for 0, 1, 2, or 3,are dissolved in diethyl ether (3 mL) and a suspension of lithiumaluminum hydride (3 mmol) in ether (5 mL) is slowly added dropwise at 0°C. The reaction mixture is heated under reflux over a period of 4 hoursand methanol followed by 1N aq. NaOH solution are slowly added dropwiseat 0° C. The reaction mixture is diluted with methanol and filtered overCelite. The solvent is removed in vacuo and the residue is purified bycolumn chromatography (SiO₂, various mixtures of dichloromethane andmethanol as mobile solvent).

4. General Instructions for the Preparation of Amines of the GeneralFormula V—C

The preparation of amines of the general formula V—C is carried out asillustrated in the following scheme 4.

Step 1

Preparation of Nitrites of the General Formula VI-D

Compounds of the general formula VI-A (1 equivalent), in which R⁸, U, T,and V have the meanings stated above and m stands for 0, 1, 2, or 3, aredissolved together with bis(triphenylphosphine)palladium dichloride (7mol %) and copper(I) iodide (14 mol %) in 1-methyl-2-pyrrolidinone (7 mLper mmol of the compound of the general formula VI-A). Following aperiod of 10 minutes the alkyne of the general formula HC≡R³⁸ (3.5equivalents) and N,N-diisopropylethylamine (2 equivalents) are added,and the reaction mixture is stirred over a period of 12 h at atemperature between 90 and 110° C. The reaction mixture is filtered overCelite and extracted with EA a number of times. The combined organicphases are washed with sat. aq. NaCl solution, dried over MgSO₄, and thesolvent is removed in vacuo. The residue is purified in each case bycolumn chromatography (SiO₂, various mixtures of hexane/EA).

5. General Instructions for the Preparation of Amines of the GeneralFormula V-D

The preparation of amines of the general formula V-D is carried out asillustrated in the following scheme 5.

Step 1 Preparation of Nitrites of the General Formula VI-E

Compounds of the general formula VI-A (1 equivalent), in which R⁸, U, T,and V have the aforementioned meanings and m stands for 0, 1, 2, or 3,are stirred with palladium dichloride (5 mol %) and a compound of thegeneral formula R³⁸—B(OH)₂ (2 equivalents), in which R³⁸ stands foraryl, heteroaryl, or cycloalkenyl, in a solvent mixture oftoluene/dioxane/2N aq. sodium carbonate solution (20 mL per 1 mmol ofcompounds of the general formula VI-A). The reaction mixture is heatedunder reflux over a period of 12 h and filtered over Celite. Thecombined organic phases are dried over magnesium sulfate, and thesolvent is removed in vacuo. The residue is purified by columnchromatography (SiO₂, various solvent mixtures of hexane and EA).

Step 2

Method 1:

Compounds of the general formula VI-E (5 mmol), in which R⁸, R³⁸, U, T,and V have the meanings stated above and m stands for 0, 1, 2, or 3,palladium-on-charcoal (10%, 500 mg) and conc. hydrochloric acid (3 mL)are dissolved in MeOH (30 mL) and exposed to a hydrogen atmosphere overa period of 6 hours at RT. The reaction mixture is filtered over Celiteand the filtrate is concentrated in vacuo. The residue is purified bymeans of flash chromatography (SiO₂, EA).

Method 2:

Compounds of the general formula VI-E (2 mmol), in which R⁸, R³⁸, U, T,and V have the meanings stated above and m stands for 0, 1, 2, or 3, aredissolved in THF (10 mL, 10 mL), and BH₃.S(CH₃)_(2 [)2.0 M in THF, 3 mL,3 equivalent] is added. The reaction mixture is heated under reflux overa period of 8 hours, aq. HCl (2N) is added and the reaction mixture isagain heated under reflux for 30 minutes. Aq. sodium hydroxide solution(2N) is added to the reaction mixture, and the mixture is washed withEA. The combined organic phases are washed with sat. aq. NaCl solutionand dried over magnesium sulfate. The solvent is removed in vacuo andthe residue is purified by column chromatography (SiO₂, various mixturesof dichloromethane and methanol as mobile solvent).

6. Preparation of Certain Acids Synthesis of2-(3-halogenated-4-(methylthio)phenyl)propanoic acids (cf. Examples 28,29)

The preparation of substituted methylthiophenylpropanoic acids isperformed as described in US2003/225283. A solution of AlCl₃ (54.9 g,412 mmol) in chloroform (180 mL) is cooled to 0° C. under argonatmosphere. A solution of methyl-2-chloro-2-oxoacetate (24.3 mL, 264mmol) in chloroform (180 mL) is added dropwise and the mixture isstirred for 30 min at 0° C. after addition. A solution of2-chlorothioanisol (39.4 g, 247 mmol) in chloroform (180 mL) is addeddropwise. The red colored reaction mixture is then slowly allowed tocome to room temperature and stirred for another 4 h. The reactionmixture is slowly poured under stirring into ice water (700 mL) and theresulting yellow mixture is stirred for another 15 min. The aluminiumsalts are filtered off and the filtrate is extracted withdichloromethane (3×50 mL). The combined organic layers are washed with asaturated aqueous solution of sodium bicarbonate (50 mL) and dried overMgSO₄. The organic solvents are removed under vacuo and methyl2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetate can be obtained as an oil(36.4 g, 60%) (a).

A solution of this ester (61.7 g, 252 mmol) in toluene (120 mL) isheated to 50° C. Aqueous NaOH (3M, 105 mL, 313 mmol) is added dropwisein the manner that the temperature does not exceed 60° C. After completeaddition, the mixture is stirred for another 1.5 h at 50° C. The sourceof heating is removed and HCl (10.6 mL, 290 mmol) is added dropwise tothe warm reaction mixture. The mixture is stirred for another 16 h atroom temperature. The formed precipitate is filtered off, washed withwater (50 mL) and toluene (50 mL) and dried. The desired(2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetic acid is obtained in thismanner as a white solid (57.2 g, 98%) (b).

Hydrazine hydrate (8.5 mL, 273 mmol) is cooled to −50° C. The oxoaceticacid (12.6 g, 54.6 mmol) obtained from (b) is added in one portionresulting in a rise of the temperature. The resulting milky mixture isheated to 80° C. and after removal of the source of heating KOH (2.09 g,31.7 mmol) is added in one portion which results in an exothermicreaction. The mixture is allowed to cool to 80° C. and then a secondportion of KOH (2.09 g, 31.7 mmol) is added, followed by cooling to 80°C. This procedure is repeated twice. Once KOH has been added the fourthtime, the reaction mixture is heated for 16 h at 100° C. The homogeneousreaction mixture is then cooled to room temperature, diluted with water(12 mL) and transferred to a separatory funnel. Water (12 mL) anddiethyl ether (40 mL) are added and the layers are separated. Theorganic layer is extracted with water (2×15 mL). Heptane is added to thecombined aqueous layers and the mixture is stirred vigorously. At aconstant temperature below 50° C. using an ice bath, HCl (conc., 26 mL)is added within 30 min and the resulting suspension is stirred for 3 hat room temperature. The formed precipitate is filtered out and washedwith aqueous HCl (2×6 mL), heptane (1×12 mL) and heptane/diethyl ether(15 mL, 4:1) and dried. 2-(3-chloro-4-(methylthio)phenyl)acetic acid(10.48 g, 89%) can be obtained as a creamy colored solid (c).

2-(3-chloro-4-(methylthio)phenyl)acetic acid is then alkylated inalpha-position analogous to Vazquez et al. (Eur. J. Med. Chem. Chim.Ther. (1997), 32, 6, 529-53). A solution of the acid (1.05 mmol) in dryTHF (3 mL) is cooled to −78° C. under an argon atmosphere and stirred.Within 15 min, a solution of LDA in hexane (2 M, 1.6 mL, 3.2 mmol) andTMEDA (0.3 mL, 1.9 mmol) is added dropwise and the resulting mixture isslowly stirred for 3 h at −78° C. Methyl iodide (0.17 mL, 2.7 mmol) isadded slowly under stirring and the mixture is stirred for another 16 hat room temperature. The reaction mixture is then neutralized applying asaturated aqueous solution of NH₄Cl (10 mL). The organic layer isseparated and the aqueous alkaline one is acidified with HCl (5 N) andthen extracted with diethyl ether (3×20 mL). The combined organic layersare dried over Na₂SO₄ and then concentrated in vacuo. Purification ofthe crude product by column chromatography (hexane/ethyl acetate 4:1)yields the desired 2-(3-chloro-4-(methylthio)phenyl)propanoic acid (d).

Synthesis of 2-(3-halogenated-4-(methylsulfonyl)phenyl)propanoic Acids(cf. Examples 29, 31)

In analogy to a described method in US2003/225283 themethylthiophenylpropanoic acids are transformed to the correspondingmethylsulfonylphenylpropanoic acids. A solution of a methylthiophenylpropanoic acid (0.16 mmol) in formic acid (0.19 mL, 4.8 mmol) is cooledto 0° C. Aqueous H₂O₂ (30%, 0.10 mL, 0.8 mmol) is added at 0° C. and themixture is stirred for 30 min. The reaction mixture is then quenchedapplying an aqueous solution of NaHSO₃ (10%), diluted with water (5 mL)and extracted with ethyl acetate (2×5 mL). The combined organic layersare dried over Mg₂SO₄ and the organic solvents are removed under vacuo.The residue is dissolved in methanol (1 mL). A solution of KMnO₄ (0.028g, 0.176 mmol) in water (0.5 mL) is added dropwise and the resultingdark brown colored reaction mixture is stirred at room temperature for30 min and then diluted with methanol (10 mL). The mixture is filteredand the filtrate is concentrated in vacuo and the crude product ispurified by column chromatography (hexane/ethyl acetate 1:4). (a).

Synthesis of 2-(4-(N-substituted sulfamoyl)-3-fluorophenyl)propanoicAcids (cf. Example 32)

In analogy to Greig, I R et al. (J. Med. Chem. (2006), 49, 4787-7492)the corresponding bromo-fluorobenzene-sulfonyl chloride (5 mmol) anddimethylamine are dissolved in dichloromethane (15 mL). Pyridine (5mmol) is added and the resulting mixture is stirred for 2 h at roomtemperature. After addition of water (15 mL), the organic layer isseparated and extracted with ethyl acetate (15 mL). The combined organiclayers are dried over Na₂SO₄ and then concentrated in vacuo. The crudeproduct is purified by column chromatography (a).

In analogy to Durandetti, M. et al. (Tetrahedron (2007), 63, 1146-1153)the corresponding sulfamoyl-arylbromide is transformed into asulfamoyl-arylpropanoic acid ester by applying ethyl chloropropionate.

A sulfamoyl-arylbromide (10 mmol) and ethyl 2-chloropropionate (1.6 mL,13 mmol) are stirred in DMF (15 mL) under a nitrogen atmosphere at roomtemperature. Mn (1.1 g, 20 mmol), (2,2′-bipyridine)nickel(II)-dibromide(0.26 g, 0.7 mmol) and TFA (20 mL) are added and the reaction mixture isstirred for 1.5 h at 50° C. The reaction mixture is cooled andhydrolyzed by HCl (1 N, 25 mL). The resulting mixture is extracted withdiethyl ether (3×25 mL) and the combined organic layers are washed withwater (25 mL), saturated aqueous NaCl (25 mL), dried over MgSO₄ andreduced in vacuo. The precipitated solid is filtered off and washed withdiethyl ether. The crude product is purified by column chromatography(b).

The propionate from (b) is dissolved in a mixture of THF (1.6 mL, 20mmol) and water (0.8 mL, 45 mmol). LiOH (0.058 g, 2.43 mmol) is addedand the reaction mixture is refluxed over night. Water (25 mL) anddiethyl ether (25 mL) are added and the layers are separated. Theaqueous one is acidified with HCl and extracted with dichloromethane(3×25 mL). The combined organic layers are dried over MgSO₄ andconcentrated in vacuo to yield the N-substituted sulfamoyl-fluorophenylpropanoic acid (c).

Synthesis of 2-(4-methoxy and hydroxy-3,5-dimethylphenyl)propanoic Acids(cf. Examples 35-38)

In analogy to a method described in WO2006/078834, phenylpropanoic acidscan be obtained starting from aryl bromides and diethyl malonate.

In the first step NaH (60%, 1.45 g, 36.2 mmol) is added to a slowlystirred solution of an aryl bromide (16.5 mmol), CuBr (4.72 g, 32.9mmol) and diethyl malonate (5 mL, 32.9 mmol) in 1,4-dioxane (20 mL) atroom temperature. The reaction mixture is stirred for 16 h at 100° C.The mixture is filtered, the filtrate is concentrated in vacuo and theresidue is purified by column chromatography (hexane/ethyl acetate 4:1)(a). Phenylmalonic acid diethylester (21 mmol) is dissolved in a mixtureof aqueous NaOH (2N) and a mixture of THF and water (1:1) (20 mL). Theresulting mixture is refluxed for 3 h, acidified with HCl (conc.) up topH 1 and stirred for another hour. Aqueous NaOH (1N) is used to alkalizeup to a pH of 13. The mixture is extracted with diethyl ether. Theaqueous layer is acidified with HCl up to pH 5 and then extracted withethyl acetate (3×). The combined organic layers are washed with asaturated aqueous solution of NaCl and dried over Na₂SO₄. The organicsolvent was removed under reduced pressure (b).

Phenylacetic acid is then alkylated in alpha-position analogous toVazquez et al. (Eur. J. Med. Chem. Chim. Ther. (1997), 32, 6, 529-53).

A solution of the acid (1.05 mmol) in dry THF (3 mL) is cooled to −78°C. under an argon atmosphere and stirred. Within 15 min, a solution ofLDA in hexane (2 M, 1.6 mL, 3.2 mmol) and TMEDA (0.3 mL, 1.9 mmol) isadded dropwise and the resulting mixture is slowly stirred for 3 h at−78° C. Methyl iodide (0.17 mL, 2.7 mmol) is added slowly under stirringand the mixture is stirred for another 16 h at room temperature. Thereaction mixture is then neutralized utilizing a saturated aqueoussolution of NH₄Cl (10 mL). The organic layer is separated and theaqueous alkaline one is acidified with HCl (5 N) and then extracted withdiethyl ether (3×20 mL). The combined organic layers are dried overNa₂SO₄ and then concentrated in vacuo. Purification of the crude productby column chromatography (hexane/ethyl acetate 4:1) yields the desiredsubstituted phenylmethoxypropanoic acid (c).

According to a procedure known to a person skilled in the art, themethoxyether group can be cleaved by HBr in acetic acid and thecorresponding phenylhydroxy-propanoic acid can be obtained.

Synthesis of 2-(4-amino-3,5-difluorophenyl)propanoic Acid (cf. Example26)

KOtBu (3.57 g, 31.85 mmol) was dissolved in DMF (30 mL) and cooled to−45° C. To this solution a mixture of ethyl 2-chloropropionate (2 mL,15.9 mmol) and 2,6-difluoronitrobenzene (2.5 g, 15.7 mmol) was addedslowly dropwise at −40° C. The resulting solution was stirred for 1 h.The reaction mixture was then acidified with HCl (16%) up to pH 4 anddiluted with water (150 mL) afterwards. The mixture was extracted withethyl acetate (3×50 mL) and the combined organic layers were washed withwater (50 mL) and a saturated aqueous solution of NaCl (2×50 mL) anddried over MgSO₄. The organic solvents were removed in vacuo and theproduct could be obtained as an oil (4.12 g, 99%) (a).

Difluoronitropropanoate (2.59 g, 10 mmol) was dissolved in EtOH/ethylacetate (200 mL, 1:1) and then hydrogenated in an H-cube (1 bar, 25° C.,1 mL/min, 0.25 mol/L). The solvents were removed in vacuo and thedifluoroaminopropanoate could be obtained as an oil (2.27 g, 99%) (b).

The crude product obtained from (b) (1 g, 4.36 mmol) was dissolved in amixture of THF and water (10 mL, 2:1). LiOH (0.312 g, 13.1 mmol) wasadded and the reaction mixture was refluxed for 16 h. Water (50 mL) anddiethyl ether (25 mL) were added and the layers were separated. Theaqueous one was acidified with HCl (pH 2) and extracted withdichloromethane (3×50 mL). The combined organic layers were dried overMgSO₄ and concentrated in vacuo. The product was obtained as a whitesolid (0.72 g, 81%) (c).

7. General Instructions for the Reaction of Amines of the GeneralFormulas V or X with Carboxylic Acids of the General Formula VII

Method A:

The acid of the general formula VII (1 equivalent), the amine of thegeneral formulas V or X (1.2 equivalents) and EDCI (1.2 equivalents) arestirred in DMF (10 mmol of acid in 20 mL) over a period of 12 hours atRT, and water is then added. The reaction mixture is extracted with EA anumber of times, the aqueous phase is saturated with NaCl and then againextracted with EA. The combined organic phases are washed with 1Nhydrochloric acid and sat. aq. NaCl soln., dried over MgSO₄, and thesolvent is removed in vacuo. The residue is purified by means of flashchromatography (SiO₂, EA/hexane 1:2).

Method B:

The acid of the general formula VII (1 equivalent) and the amine of thegeneral formula V or X (1.1 equivalents) are dissolved in DCM (1 mmolacid in 6 mL), and to the solution EDCI (1.5 equivalents), HOBt (1.4equivalents) and Triethylamine (3 equivalents) are added at 0° C. Thereaction mixture is stirred at RT for a period of 20 h and purified bycolumn chromatography (2:1 mixture of n-hexane/AE).

The following example compounds were obtained in accordance with methodB above.

Example Compound 32-(4-Amino-3-bromo-5-methoxyphenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

¹H-NMR (CDCl₃) δ 7.52 (d, 1H, J=7.5 Hz), 7.21 (d, 1H, J=7.5 Hz), 6.93(d, 1H, J=1.4 Hz), 6.57 (d, 1H), 6.24 (bt, NH), 4.47 (d, 2H), 4.22 (s,2H), 3.80 (s, 3H), 3.51 (s, 2H), 3.30-3.26 (m, 2H), 1.70-1.48 (m, 3H),1.21-1.09 (m, 2H), 0.95 (d, 3H, J=6.4 Hz)

IR 3298, 2924, 1649, 1575, 1500, 1460, 1420, 1338, 1135, 1047 cm⁻¹

Mass (FAB) m/z 515 and 517 [M+H]⁺ (Base), 537 and 539 [M+Na]⁺

Example Compound 42-(3-Fluorophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

IR (KBr) 3272, 2923, 1648, 1592, 1552, 1455, 1421, 1374, 1337, 1246,1138, 958, 835, 774 cm⁻¹

MS (FAB) m/z 410 (M+H)

Example Compound 52-(2,4-Difluorophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

IR (KBr) 3270, 2921, 1647, 1558, 1507, 1424, 1330, 1242, 1134, 966, 851cm⁻¹

MS (FAB) m/z 428 (M+H)

Example Compound 62-(2,6-Difluorophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

IR (KBr) 3292, 2924, 1656, 1593, 1553, 1468, 1419, 1337, 1238, 1178,1135, 1017, 945, 834, 784 cm⁻¹

MS (FAB) m/z 428 (M+H)

Example Compound 72-(2,5-Difluorophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

IR (KBr) 3271, 2922, 1644, 1593, 1555, 1497, 1424, 1329, 1137, 960, 833,756 cm⁻¹

MS (FAB) m/z 428 (M+H)

Example Compound 82-(4-Fluorophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

IR (KBr) 3255, 2920, 1646, 1595, 1558, 1509, 1424, 1330, 1229, 1132,1043, 960, 828, 755 cm⁻¹

MS (FAB) m/z 410 (M+H)

Example Compound 92-(4-Hydroxy-3-methoxyphenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)propionamide

¹H NMR (300 M Hz, CDCl₃) δ7.44 (d, 1H, J=7.7 Hz), 7.17 (d, 1H, J=7.5Hz), 6.88 (d, 1H, J=7.9 Hz), 6.80-6.70 (m, 2H), 6.11 (bt, 1H), 5.60 (s,1H), 4.46-4.42 (m, 2H), 3.84 (s, 3H), 3.55 (q, 1H, J=7.1 Hz), 3.32-3.23(m, 2H), 2.83-2.73 (m, 2H), 1.71-1.66 (m, 2H), 1.53 (d, 3H, J=7.1 Hz),1.26-1.1 (m, 2H), 0.96 (d, 3H, J=6.6 Hz)

IR (KBr) 3301, 2925, 1650, 1516, 1458, 1421, 1373 cm⁻¹ MS (FAB) m/z 452(M+H)

Example Compound 102-(3,5-Difluorophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)propionamide

¹H NMR (300 M Hz, CDCl₃) δ 7.47 (d, 1H, J=7.5 Hz), 7.21 (d, 1H, J=7.7Hz), 6.85-6.82 (m, 2H), 6.80-6.70 (m, 2H), 6.11 (bt, 1H), 5.60 (s, 1H),4.46-4.42 (m, 2H), 3.84 (s, 3H), 3.55 (q, 1H, J=7.1 Hz), 3.32-3.23 (m,2H), 2.83-2.73 (m, 2H), 1.71-1.66 (m, 2H), 1.53 (d, 3H, J=7.1 Hz),1.26-1.1 (m, 2H), 0.96 (d, 3H, J=6.6 Hz)

IR (KBr) 3293, 2925, 1651, 1596, 1542, 1460, 1335 cm⁻¹ MS (FAB) m/z 442(M+H)

Example Compound 122-(4-Fluorophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)propionamide

¹H-NMR (CDCl₃) δ 7.43 (d, 1H, J=7.5 Hz), 7.28-7.24 (m, 2H), 7.18 (d, 1H,J=7.7 Hz), 7.06-7.00 (m, 2H), 6.16 (bs, NH), 4.45 (d, 2H), 3.59 (q, 1H,J=7.0 Hz), 3.29 (m, 2H), 2.79 (m, 2H0, 1.75-1.50 (m, 3H), 1.53 (d, 3H,J=7.1 Hz), 1.26-1.10 (m, 2H), 0.96 (d, 3H, J=6.4 Hz)

IR 3291, 2925, 1650, 1510, 1458, 1419, 1336, 1231, 1177, 1138 cm⁻¹

Mass (FAB) m/z 424 [M+H]⁺ (Base), 446 [M+Na]⁺

Example Compound 132-(3-Fluorophenyl)N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)propionamide

¹H-NMR (CDCl₃) δ 7.43 (d, 1H, J=7.7 Hz), 7.31 (m, 1H), 7.18 (d, 1H,J=7.7 Hz), 7.07-6.95 (m, 3H), 6.23 (bs, NH), 4.45 (d, 2H), 3.60 (q, 1H,J=7.0 Hz), 3.29 (m, 2H), 2.79 (m, 2H), 1.65-1.50 (m, 3H), 1.54 (d, 2H,J=7.0 Hz), 1.24-1.12 (m, 2H), 0.96 (d, 3H, J=6.4 Hz)

IR 3292, 2925, 1651, 1592, 1542, 1456, 1419, 1177, 1140 cm⁻¹

Mass (FAB) m/z 424 [M+H]⁺ (Base), 446 [M+Na]⁺

Example Compound 142-(3,4-Diaminophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)propionamide

¹H-NMR (CDCl₃) δ7.42 (d, 1H, J=7.5 Hz), 7.17 (d, 1H, J=7.7 Hz),6.67-6.57 (m, 3H), 6.03 (bt, NH), 4.41 (d, 2H), 3.49 (q, 1H, J=7.3 Hz),3.40 (br, NH₂), 3.33-3.27 (m, 2H), 2.84-2.74 (m, 2H), 1.73-1.55 (m, 3H),1.51 (d, 3H, J=7.1 Hz), 1.30-1.18 (m, 2H), 0.96 (d, 3H, J=6.6 Hz)

IR 3334, 2925, 1651, 1518, 1419, 1176, 1135, 733 cm⁻¹

Mass (FAB) m/z 436 [M+H]⁺

Example Compound 15N-(2-Butoxy-6-tert-butylpyridin-3-ylmethyl)-2-(3,4-diaminophenyl)propionamide

¹H-NMR (CDCl₃) δ 7.32 (d, 1H, J=7.5 Hz, Ar), 6.76 (d, 1H, J=7.3 Hz, Ar),6.66-6.57 (m, 3H, Ar), 6.00 (bt, NH), 4.27 (m, 4H, OCH₂ & CH₂NH), 3.41(q, 1H, J=7.1 Hz, CHCH₃), 1.64 (m, 2H, OCH₂CH₂), 1.45 (d, 3H, J=7.1 Hz,CHCH₃), 1.39 (m, 2H, CH₂CH₃), 1.29 (s, 9H, C(CH₃)₃), 0.95 (t, 3H, J=7.3Hz, CH₂CH₃)

IR 3303, 2960, 1649, 1517, 1456, 1254 cm⁻¹

Mass (FAB) 399 m/z [M+H]⁺

Example Compound 16N-(6′-tert-Butyl-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)-2-(3,4-diaminophenyl)propionamide

¹H-NMR (CDCl₃) δ 7.26 (d, 1H, J=7.9 Hz, Ar), 6.85 (d, 1H, J=7.7 Hz, Ar),6.66-6.58 (m, 3H, Ar), 6.39 (bt, NH), 4.37 (m, 2H, CH₂NH), 3.45 (q, 1H,J=7.1 Hz, CHCH₃), 3.37 (bs, NH₂*2), 3.23 (m, 2H, piperidine), 2.74 (m,2H, piperidine), 1.65-1.45 (m, 3H, piperidine), 1.49 (d, 3H, J=7.1 Hz,CHCH₃), 1.29 (s, 9H, C(CH₃)₃), 1.28-1.16 (m, 2H, piperidine), 0.95 (d,3H, J=6.4 Hz, piperidine CH₃)

IR 3338, 2955, 1648, 1517, 1449, 1232 cm⁻¹

Mass (FAB) m/z 424[M+H]⁺

Example Compound 17N-(6-tert-Butyl-2-cyclohexylsulfanylpyridin-3-ylmethyl)-2-(3,4-diaminophenyl)-propionamide

¹H-NMR (CDCl₃) δ 7.27 (d, 1H, Ar), 6.91 (d, 1H, J=7.9 Hz, Ar), 6.67-6.59(m, 3H, Ar), 5.90 (bt, NH), 4.26 (m, 2H, CH₂NH), 3.96 (m, 1H, SCH), 3.46(q, 1H, J=7.3 Hz, CHCH₃), 3.37 (bs, NH₂*2), 2.06 (m, 2H, cyclohexyl),1.80-1.20 (m, 8H, cyclohexyl), 1.50 (d, 3H, CHCH₃), 1.31 (s, 9H,C(CH₃)₃)

IR 3303, 2929, 2854, 1651, 1517, 1444, 1079 cm⁻¹

Mass (FAB) m/z 441 [M+H]⁺

Example Compound 192-(3,5-Dibromo-4-hydroxyphenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetra-hydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)propionamide

¹H-NMR (CDCl₃) δ 7.48 (m, 1H, Ar), 7.39 (s, 2H, Ar), 7.22 (d, 1H, J=7.7Hz, Ar), 6.27 (bt, NH), 4.47 (m, 2H, CH₂NH), 3.46 (q, 1H, J=7.1 Hz,CHCH₃), 3.31 (m, 2H, piperidine), 2.81 (m, 2H, piperidine), 2.40 (s,OH), 1.75-1.16 (m, 5H, piperidine), 1.50 (d, 3H, J=7.1 Hz, CHCH₃), 0.98(d, 3H, J=6.4 Hz, piperidine CH₃)

IR 3298, 2924, 1650, 1550, 1462, 1417, 1176, 1138 cm⁻¹

Mass (FAB) m/z 580 [M+H]⁺

Example Compound 202-(4-Amino-3,5-dibromophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetra-hydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)propionamide

¹H-NMR (CDCl₃) δ 7.47 (d, 1H, J=7.7 Hz, Ar), 7.31 (s, 2H, Ar), 7.21 (d,1H, J=7.7 Hz, Ar), 6.18 (bt, NH), 4.55 (bs, NH₂), 4.46 (m, 2H, CH₂NH),3.43 (q, 1H, J=7.0 Hz, CHCH₃), 3.30 (m, 2H, piperidine), 2.81 (m, 2H,piperidine), 1.75-1.15 (m, 5H, piperidine), 1.48 (d, 3H, J=7.1 Hz,CH₂CH₃), 0.97 (d, 3H, J=6.4 Hz, piperidine CH₃)

IR 3298, 2924, 1649, 1544, 1474, 1418, 1177, 1136 cm⁻¹

Mass (FAB) m/z 579[M+H]⁺

Example Compound 212-(3-Bromo-4-hydroxy-5-methoxyphenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

¹H-NMR (CDCl₃) δ 7.54 (d, 1H, J=7.5 Hz, Ar), 7.22 (d, 1H, J=7.7 Hz, Ar),6.99 (d, 1H, J=1.5 Hz, Ar), 6.69 (d, 1H, J=2.0 Hz, Ar), 6.27 (bt, NH),5.91 (bs, OH), 4.48 (m, 2H, CH₂NH), 3.86 (s, 3H, OCH₃), 3.53 (s, 2H,CH₂CO), 3.28 (m, 2H, piperidine), 2.80 (m, 2H, piperidine), 1.73-1.07(m, 5H, piperidine), 0.96 (d, 3H, J=6.4 Hz, piperidine CH₃)

IR 3298, 2924, 1649, 1501, 1459, 1421, 1282, 1178, 1136, 1047 cm⁻¹

Mass (FAB) m/z 517[M+H]⁺

Example Compound 222-(4-Amino-3,5-dibromophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetra-hydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

¹H-NMR (CDCl₃) δ 7.53 (d, 1H, J=7.3 Hz, Ar), 7.29 (s, 2H, Ar), 7.23 (d,1H, J=7.7 Hz, Ar), 6.26 (bt, NH), 4.57 (bs, NH₂), 4.48 (m, 2H, CH₂NH),3.46 (s, 2H, CH₂CO), 3.30 (m, 2H, piperidine), 2.81 (m, 2H, piperidine),1.75-1.10 (m, 5H, piperidine), 0.97 (d, 3H, J=6.4 Hz, piperidine CH₃)

IR 3288, 2923, 1649, 1544, 1478, 1418, 1337, 1177, 1135 cm⁻¹

Mass (FAB) m/z 565 [M+H]⁺

Example Compound 232-(3,5-Dibromo-4-hydroxyphenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetra-hydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

¹H-NMR (CDCl₃) δ 7.55 (d, 1H, J=7.7 Hz, Ar), 7.38 (s, 2H, Ar), 7.24 (d,1H, J=7.7 Hz, Ar), 6.31 (bt, NH), 4.50 (m, 2H, CH₂NH), 3.50 (s, 2H,CH₂CO), 3.31 (m, 2H, piperidine), 2.82 (m, 2H, piperidine), 2.40 (s,OH), 1.77-1.10 (m, 5H, piperidine), 0.97 (d, 3H, J=6.6 Hz, piperidineCH₃)

IR 3297, 2924, 1650, 1546, 1473, 1419, 1337, 1177, 1137 cm⁻¹

Mass (FAB) m/z 566 [M+H]⁺

Example Compound 242-(3-Amino-4-hydroxyphenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)propionamide

¹H-NMR (CDCl₃) δ 7.42 (d, 1H, J=7.7 Hz, Ar), 7.17 (d, 1H, J=7.7 Hz, Ar),6.69-6.64 (m, 2H, Ar), 6.53 (dd, 1H, J=8.0, 1.8 Hz, Ar), 6.07 (bt, NH),4.42 (d, 2H, J=5.7 Hz, CH₂NH), 3.69 (bs, NH₂), 3.59 (q, 1H, J=7.1 Hz,CHCH₃), 3.30 (m, 2H, piperidine), 2.79 (m, 2H, piperidine), 1.71-1.50(m, 6H, piperidine & CHCH₃), 1.22 (m, 2H, piperidine), 0.96 (d, 3H,J=6.6 Hz, CHCH₃)

IR 3298, 2924, 1649, 1519, 1458, 1420, 1177, 1136 cm⁻¹

Mass (FAB) m/z 437 [M+H]⁺, 459 [M+Na]⁺

Example Compound 252-(3,5-Dibromophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide

¹H-NMR (CDCl₃) δ 7.61 (t, 1H, J=1.7 Hz), 7.54 (d, 1H, J=7.7 Hz), 7.38(d, 1H, J=1.7 Hz), 7.24 (d, 1H, J=7.7 Hz), 6.34 (bt, NH), 4.50 (d, 2H),3.54 (s, 3H), 3.32 (m, 2H), 2.83 (m, 2H), 1.75-1.50 (m, 3H), 1.33-1.13(m, 2H), 0.98 (d, 3H, J=6.4 Hz)

IR 3291, 2924, 1649, 1554, 1458, 1421, 1337, 1176, 1138 cm⁻¹

Mass (FAB) m/z 550[M+H]⁺

The following example compounds were obtained according to the methodsdescribed above:

 [1] 2-(4-Amino-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide  [2]2-(3,5-Dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide [11]2-(3,4-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide [18]2-(4-Acetamido-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide [19]2-(3,5-Dibromo-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide [26]2-(4-Amino-3,5-difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide [27]2-(3-Fluoro-5-hydroxy-4-nitrophenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide [33]N-(2-Fluoro-4-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluormethyl)pyridin-3-yl)methylamino)-1-oxopropane-2-yl)phenyl)acrylamide [34]N-(2-Fluoro-6-iodo-4-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl)methylamino)-1-oxopropane-2-yl)phenyl)acrylamide

Example compounds 28-32 and 35-38 may also be obtained according to themethods described above.

Pharmacological Data

The affinity of the compounds of the invention for the vanilloidreceptor 1 (VR1/TRPV1-Receptor) was detected as described above(Pharmacological Methods I and II respectively).

The compounds of the invention of the above formula I show excellentaffinity to the VR1/TRPV1 receptor (Table 1).

TABLE 1 IC₅₀ (Human) [nM] Compound of K_(i) (Rat) K_(i) (Human)following pH- Example Capsaicin [nM] Capsaicin [nM] stimulus 2 60.1 40.6ne 3 16.7 4.4 253 4 80 34 ne 6 118 38 ne 7 63 30 ne 10 24.7 ne 18 25 ne19 1.1 31% @ 10 μM; 20% @ 5 μM; 0% @ 1 μM 20 0.9 27% @ 10 μM; 10% @ 5μM; 0% @ 1 μM 21 0.1 38% @ 10 μM; 4% @ 5 μM; 22 0.7 158 23 0.3 35% @ 10μM; 8% @ 5 μM; 26 3.4 9.6 ne 27 7.7 7.9 49% @ 10 μM; 35% @ 5 μM; 7% @ 1μM 34 4.8 ne Ne denotes “no effect”, i.e. no reaction was observed. Thevalue following the symbol “@” indicates the concentration at which theinhibition (in percent) was determined.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

What is claimed is:
 1. A compound corresponding to formula I:

wherein n is 0, 1, 2, 3, or 4; R¹ represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰; —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶; —S(═O)₂—R²⁷ or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; R² represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰; —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶; —S(═O)₂—R²⁷ or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; R³ represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶; —S(═O)₂—R²⁷ or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; R⁴ represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰; —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶; —S(═O)₂—R²⁷ or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; R⁵ represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —C(═NH)—NH₂; —C(═NH)—NH—R⁹; —O—P(═O)₂—O—R¹²; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰; —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶; —S(═O)₂—R²⁷ or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; R⁶ represents hydrogen or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; R⁷ represents hydrogen or —OH; or R⁶ and R⁷ together with the carbon atom to which they are attached form a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted three-membered, four-membered, five-membered, or six-membered cycloaliphatic group; R⁸ represents —CF₃; or an unsubstituted tert-butyl group; T stands for C—R³⁵; U stands for C—R³⁶; V stands for N, and W represents C—R³⁸; or T stands for C—R³⁵; U stands for N, V stands for C—R³⁷, and W stands for C—R³⁸; R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶ and R²⁷, each independently represent a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; or an unsaturated or saturated, unsubstituted, monosubstituted or polysubstituted, three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered cycloaliphatic group optionally containing at least one heteroatom as a ring member, wherein said cycloaliphatic group optionally may be condensed with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted monocyclic or polycyclic ring system, or said cycloaliphatic group optionally may be bonded via a linear or branched, unsubstituted, monosubstituted or polysubstituted C₁₋₆ alkylene group or two to six-membered heteroalkylene group, or both; or an unsubstituted, monosubstituted or polysubstituted five-membered to fourteen-membered aryl group or heteroaryl group, which optionally may be condensed with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted monocyclic or polycyclic ring system, or which optionally may be bonded via a linear or branched, unsubstituted, monosubstituted or polysubstituted C₁₋₆ alkylene group or two to six-membered heteroalkylene group, or both; R³⁵, R³⁶, and R³⁷ each independently represent H; —SF₅; —NO₂; —CF₃; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —C(═O)—NHR¹⁸; —C(═O)—NR¹⁹R²⁰; —S(═O)₂—NHR²¹; —S(═O)₂—NR²²R²³; —C(═O)—OR²⁴; —C(═O)—R²⁵; —S(═O)—R²⁶; or —S(═O)²R²⁷; or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; or an unsubstituted, monosubstituted or polysubstituted five-membered to fourteen-membered aryl group or heteroaryl group, which optionally may be condensed with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted monocyclic or polycyclic ring system, or optionally may be bonded via a linear or branched, unsubstituted, monosubstituted or polysubstituted C₁₋₆ alkylene group or C₂₋₆ alkenylene group or C₂₋₆-alkynylene group, or both; R³⁸ represents —SF₅; —NO₂; —CF₃; —CF₂ Cl; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; and —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —NHR³⁹; —NR⁴⁰R⁴¹; —OR⁴²; —SR⁴³; —C(═O)—NHR⁴⁴; —C(═O)—NR⁴⁵R⁴⁶; and —S(═O)₂—NHR⁴⁷; —S(═O)₂—NR⁴⁸R⁴⁹; —C(═O)—OR⁵⁰; —C(═P)—R⁵¹; —S(═O)—R⁵²; —S(═O)₂—R⁵³; —C(═NH)—NH₂; —C(═NH)—NH—R⁵⁴; —N═C(NH₂)₂; or —N═C(NHR⁵⁵)—(NHR⁵⁶); or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; or an unsaturated or saturated, unsubstituted, monosubstituted or polysubstituted three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered cycloaliphatic group optionally containing at least one heteroatom as ring member, wherein said cycloaliphatic group is bonded to the parent structure via a carbon atom in the ring thereof, and optionally may be condensed with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted monocyclic or polycyclic ring system, or optionally may be bonded via a linear or branched, unsubstituted, monosubstituted or polysubstituted C₁₋₆ alkylene group or C₂₋₆ alkenylene group or C₂₋₆ alkynylene group, or both; or an unsubstituted, monosubstituted or polysubstituted five-membered to fourteen-membered aryl or heteroaryl group, which optionally may be condensed with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted monocyclic or polycyclic ring system, or optionally may be bonded via a linear or branched, unsubstituted, monosubstituted or polysubstituted C₁₋₆ alkylene group or C₂₋₆ alkenylene group or C₂₋₆-alkynylene group, or both; R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ each independently represent a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; or an unsaturated or saturated, unsubstituted, monosubstituted or polysubstituted, three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered cycloaliphatic group optionally containing at least one heteroatom as ring member, wherein said cycloaliphatic group optionally may be condensed with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted monocyclic or polycyclic ring system, or optionally may be bonded via a linear or branched, unsubstituted, monosubstituted or polysubstituted C₁₋₆ alkylene group or two to six-membered heteroalkylene group; or both; or an unsubstituted, monosubstituted or polysubstituted five-membered to fourteen-membered aryl or heteroaryl group, which optionally may be condensed with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted monocyclic or polycyclic ring system, or optionally may be bonded via a linear or branched, unsubstituted, monosubstituted or polysubstituted C₁₋₆ alkylene group or two to six-membered heteroalkylene group; or both; or R⁴⁰ and R⁴¹ together with nitrogen atom to which they are attached form a saturated or unsaturated four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered heterocycloaliphatic group, which is unsubstituted or substituted by 1, 2, 3, 4, or 5 groups R⁵⁷; which optionally contains at least one further heteroatom as ring member, and which optionally may be condensed with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted monocyclic or polycyclic ring system; R⁵⁷ represents —NHR⁵⁸, —NR⁵⁹R⁶⁰, or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; R⁵⁸, R⁵⁹, and R⁶⁰ each independently represent —C(═O)—R⁶¹; or a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; or an unsubstituted, monosubstituted or polysubstituted five-membered to fourteen-membered aryl group or heteroaryl group, which optionally may be condensed with a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted monocyclic or polycyclic ring system, or optionally may be bonded via a linear or branched, unsubstituted, monosubstituted or polysubstituted C₁₋₆ alkylene group or C₂₋₆ alkenylene group or C₂₋₆ alkynylene group; or both; and R⁶¹ represents a linear or branched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted aliphatic C₁₋₁₀ group; or a salt thereof; wherein: said aliphatic C₁₋₁₀ groups and tert-butyl groups each optionally may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO₂, —OH, —NH₂, —SH, —O(C₁₋₅ alkyl), —S(C₁₋₅ alkyl), —NH(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)-(C₁₋₅ alkyl), —C(═O)—O—(C₁₋₅ alkyl), —O—C(═O)—(C₁₋₅ alkyl), —O-phenyl, phenyl, —OCF₃, and —SCF₃; said two to six-membered heteroalkylene groups, C₁₋₆ alkylene groups, C₂₋₆ alkenylene groups, and C₂₋₆ alkynylene groups each optionally may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO₂, —OH, —NH₂, —SH, —O(C₁₋₅ alkyl), —S(C₁₋₅ alkyl), —NH(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)-(C₁₋₅ alkyl), —OCF₃, and —SCF₃; said heteroalkylene groups each optionally contain 1, 2, or 3 heteroatom(s) independently selected from the group consisting of oxygen, sulfur, and nitrogen (NH) as link(s); said (hetero)cycloaliphatic groups each optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of —(C₁₋₆ alkylene)—OH, ═CH₂, —O—(C₁₋₅ alkylene)oxetanyl, —(C₁₋₅ alkylene)—O—(C₁₋₅ alkylene)oxetanyl, —CH₂—NH—(C₁₋₅ alkyl), —CH₂—N(C₁₋₅ alkyl)₂, —N[C(═O)—(C₁₋₅ alkyl)]phenyl, —CH₂—O—(C₁₋₅ alkyl), oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—(C₁₋₅ alkyl), —O—C(═O)—(C₁₋₅ alkyl), —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—(C₁₋₅ alkyl), —(C₁₋₅ alkyl), —C(═O)—(C₁₋₅ alkyl), —C(═O)—OH, —C(═O)—O—(C₁₋₅ alkyl), —NH—(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)₂, —NH-phenyl, —N(C₁₋₅ alkyl)phenyl, cyclohexyl, cyclopentyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, piperidinyl, pyrrolidinyl, —(CH₂)pyridinyl, pyridinyl, —O-phenyl, —O-benzyl, phenyl, and benzyl; wherein the cyclic moiety of the oxetanyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, —N[C(═O)—(C₁₋₅ alkyl)]phenyl, —NH-phenyl, —N(C₁₋₅ alkyl)phenyl, —(CH₂)pyridinyl, pyridinyl, —O-phenyl, —O-benzyl, phenyl, and benzyl groups optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF₃, —SF₅, —CN, —NO₂, —(C₁₋₅ alkyl, —O—(C₁₋₅ alkyl), —O—CF₃, —S—CF₃, phenyl, and —O-benzyl; and wherein, unless otherwise stated, said (hetero)cycloaliphatic groups can each optionally exhibit 1, 2, or 3 (further) heteroatom(s) independently selected from the group consisting of oxygen, nitrogen, and sulfur; the rings of said monocyclic or polycyclic ring systems each optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—(C₁₋₅ alkyl), —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—(C₁₋₅ alkyl), —(C₁₋₅ alkyl), —C(═O)—(C₁₋₅ alkyl), —C(═O)—OH, —C(═O)—O—(C₁₋₅ alkyl), —NH—(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)₂, —O-phenyl, —O-benzyl, phenyl, and benzyl; wherein the cyclic moiety of the —O-phenyl, —O-benzyl, phenyl, and benzyl groups each optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF₃, —SF₅, —CN, —NO₂, —(C₁₋₅ alkyl), —O—(C₁₋₅ alkyl), —O—CF₃, —S—CF₃, phenyl, and —O-benzyl; the rings of said monocyclic or polycyclic ring systems are each five-membered, six-membered, or seven-membered and each optionally may contain 1, 2, 3, 4, or 5 heteroatom(s) as ring member(s), wherein said heteroatoms are independently selected from the group consisting of oxygen, nitrogen, and sulfur; said aryl or heteroaryl groups each optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—(C₁₋₅ alkyl), —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—(C₁₋₅ alkyl), —(C₁₋₅ alkyl), —C(═O)—OH, —C(═O)—O—(C₁₋₅ alkyl), —NH—(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)₂, —NH—S(═O)₂—(C₁₋₅ alkyl), —NH—C(═O)—O—(C₁₋₅ alkyl), —C(═O)—H, —C(═O)—(C₁₋₅ alkyl), —C(═O)—NH₂, —C(═O)—NH—(C₁₋₅ alkyl), —C(═O)—N—(C₁₋₅ alkyl)₂, —O-phenyl, —O-benzyl, phenyl, and benzyl; wherein the cyclic moiety of the —O-phenyl, —O-benzyl, phenyl, and benzyl groups each optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF₃, —SF₅, —CN, —NO₂, —(C₁₋₅ alkyl), —O—(C₁₋₅ alkyl), —O—CF₃, —S—CF₃, phenyl, and —O-benzyl; and said heteroaryl groups each optionally may contain 1, 2, 3, 4, or 5 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen, and sulfur as ring member(s).
 2. A compound according to claim 1, wherein said compound is in the form of an isolated stereoisomer.
 3. A compound according to claim 1, wherein said compound is in the form of a mixute of stereoisomers in any mixing ratio.
 4. A compound according to claim 1, wherein said compound is in the form of a racemic mixture.
 5. A compound according to claim 1, wherein: n is 0, 1, 2, 3, or 4; R¹ represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)—NR²²R²³; —S(═O)—R²⁶; —S(═O)₂—R²⁷; methyl; —CF₃; —CCl₃; —CBr₃; —CHF₂; —CH₂F; —CF₂Cl; —CCl₂F; ethyl; —CF₂—CH₃; —CH₂—CF₃; —C₂F₅; —CH₂—CCl₃; —CH₂—CBr₃; —CHF—CF₂Cl; —CF₂—CF₂Cl; —CFCl—CF₂Cl; n-propyl; —CF₂—CF₂—CF₃; —CF(CF₃)₂; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R² represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)—NR²²R²³; —S(═O)—R²⁶; —S(═O)₂—R²⁷; methyl; —CF₃; —CCl₃; —CBr₃; —CHF₂; —CH₂F; —CF₂Cl; —CCl₂F; ethyl; —CF₂—CH₃; —CH₂—CF₃; —C₂F₅; —CH₂—CCl₃; —CH₂—CBr₃; —CHF—CF₂Cl; —CF₂—CF₂Cl; —CFCl—CF₂Cl; n-propyl; —CF₂—CF₂—CF₃; —CF(CF₃)₂; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R³ represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)—R²⁶; —S(═O)₂—R²⁷; methyl; —CF₃; —CCl₃; —CBr₃; —CHF₂; —CH₂F; —CF₂Cl; —CCl₂F; ethyl; —CF₂—CH₃; —CH₂—CF₃; —C₂F₅; —CH₂—CCl₃; —CH₂—CBr₃; —CHF—CF₂Cl; —CF₂—CF₂Cl; —CFCl —CF₂Cl; n-propyl; —CF₂—CF₂—CF₃; —CF(CF₃)₂; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R⁴ represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)—NR²²R²³; —S(═O)—R²⁶; —S(═O)₂—R²⁷; methyl; —CF₃; —CCl₃; —CBr₃; —CHF₂; —CH₂F; —CF₂Cl; —CCl₂F; ethyl; —CF₂—CH₃; —CH₂—CF₃; —C₂F₅; —CH₂—CCl₃; —CH₂—CBr₃; —CHF—CF₂Cl; —CF₂—CF₂Cl; —CFCl—CF₂Cl; n-propyl; —CF₂—CF₂—CF₃; —CF(CF₃)₂; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R⁵ represents H; F; Cl; Br; I; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —NHR¹³; —NR¹⁴R¹⁵; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)—NR²²R²³; —S(═O)—R²⁶; —S(═O)₂—R²⁷; methyl; —CF₃; —CCl₃; —CBr₃; —CHF₂; —CH₂F; —CF₂Cl; —CCl₂F; ethyl; —CF₂—CH₃; —CH₂—CF₃; —C₂F₅; —CH₂—CCl₃; —CH₂—CBr₃; —CHF—CF₂Cl; —CF₂—CF₂Cl; —CFCl—CF₂Cl; n-propyl; —CF₂—CF₂—CF₃; —CF(CF₃)₂; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R⁶ represents hydrogen or an alkyl group selected from the group consisting of —CH₂—OH, —CH₂—CH₂—OH, —CH₂—CH₂—CH₂—OH, —CH₂—CH₂—CH₂—CH₂—OH, isopropyl, n-butyl, sec-butyl, isobutyl, methyl, ethyl, and n-propyl; R⁷ represents hydrogen or —OH; or R⁶ and R⁷ together with carbon atom to which they are attached form a cycloalkyl group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; R⁸ represents —CF₃; or an unsubstituted tert-butyl group; T represents C—R³⁵; U represents C—R³⁶; V represents N, and W represents C—R³⁸; or T represents C—R³⁵; U represents N, V represents C—R³⁷, and W represents C—R³⁸; R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²², R²³, R²⁵, R²⁶, and R²⁷ each independently represent a group selected from the group consisting of methyl, —CF₃, —CCl₃, —CBr₃, —CHF₂, —CH₂F, —CF₂Cl, —CCl₂F, —CH₂—CN, —CH₂—O—CH₃, —CH₂—O—CF₃, —CH₂—SF₃, ethyl, —CF₂—CH₃, —CH₂—CF₃, —C₂F₅, —CH₂—CCl₃, —CH₂—CBr₃, —CHF—CF₂Cl, —CF₂—CF₂Cl, —CFCl—CF₂Cl, —CH₂—CH₂—CN, n-propyl, —CF₂—CF₂—CF₃, —CF(CF₃)₂, isopropyl, —CH₂—CH₂—CH₂—CN, —CH₂—O—CH₂—CH₃, —CH₂—CH₂—SF₃, —CH₂—CH₂—OCF₃, —CH(CH₃)—(O—CH₃), —CH(CH₃)—(S—CH₃), n-butyl, —CF₂—CF₂—CF₂—CF₃, —CH₂—CH₂—CH₂—CH₂—CN, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethylhept-4-yl, 3-methylbutyl, n-hexyl, (3,3)-dimethylbutyl, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—C₂H₅, —CH₂—CH₂—CH₂—O—CH₃, ethenyl, propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, and 3-pentenyl; or a group selected from the group consisting of 2,3-dihydro-1H-indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl, each of which optionally may be bonded via a —CH₂—O—, —CH₂—CH₂—O—, —CH₂—CH₂—O—CH₂—, —CH₂—CH(CH₃)—O—CH₂—, —(CH₂)—, —(CH₂)₂bond or —(CH₂)₃ group, and each of which may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), —OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —O—CF₃, —S—CF₃, —SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃, —C(═O)—OH, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂, and —C(═O)—O—C(CH₃)₃; or a group selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, thiazolyl, oxazolyl, and isoxazolyl; each of which optionally may be bonded via a —(CH₂)—, —(CH₂)₂bond or —(CH₂)₃ group, and each of which may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—OH, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂, —C(═O)—O—C(CH₃)₃, —NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(CH₃)—(C₂H₅), —NH—C(═O)—O—CH₃, —NH—C(═O)—O—C₂H₅, —NH—C(═O)—O—C(CH₃)₃, —C(═O)—H, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃, —C(═O)—NH₂, —C(═O)—NH—CH₃, —C(═O)-nH-C₂H₅, —C(═O)—N(CH₃)₂, —C(═O)—N(C₂H₅)₂, —O-phenyl, —O-benzyl, phenyl, and benzyl; R³⁵, R³⁶, and R³⁷ each independently represent H; —SF₅; —NO₂; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; and —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —NHR¹³; —NR¹⁴R¹⁵; OR¹⁶; —SR¹⁷; —S(═O)—R²⁵; —S(═O)₂—R²⁶; —CH₂—OH; methyl; —CF₃; —CCl₃; —CBr₃; —CHF₂; —CH₂F; —CF₂Cl; —CCl₂F; ethyl; —CF₂—CH₃; —CH₂—CF₃; —C₂F₅; —CH₂—CCl₃; —CH₂—CBr₃; —CHF—CF₂Cl; —CF₂—CF₂Cl; —CFCl—CF₂Cl; n-propyl; —CF₂—CF₂—CF₃; —CF(CF₃)₂; isopropyl; n-butyl; sec-butyl; isobutyl, or tert-butyl; or a phenyl group which may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; R³⁸ represents —SF₅; —NO₂; —CN; —NH₂; —OH; —SH; —C(═O)—NH₂; —S(═O)₂—NH₂; —C(═O)—NH—OH; —C(═O)—OH; —C(═O)—H; —S(═O)₂—OH; —NHR³⁹; —NR⁴⁰R⁴¹; —OR⁴²; —SR⁴³; —C(═O)—OR⁵⁰; and —S(═O)—R⁵²; —S(═O)₂—R⁵³; —C(═NH)—NH₂; —C(═NH)—NH—R⁵⁴; —N═C(NH₂)₂; or —N═C(NHR⁵⁵)—(NHR⁵⁶); or a cyclic group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl, each of which is bonded to the basic framework via a carbon atom of the rings thereof, optionally via a —(CH═CH)—, —C≡C or —C≡C—CH₂— group, and each of which may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of —CN, —CH₂—N(CH₃)₂, —CH₂—N(C₂H₅)₂, —CH₂—NH—CH₃, —CH₂—NH—C₂H₅, —N—[C(═O)—C₂H₅]phenyl, —N—[C(═O)—CH₃]phenyl, oxo (═O), thioxo (═S), —OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —O—CF₃, —S—CF₃, —SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃, —C(═O)—OH, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂, and —C(═O)—O—C(CH₃)₃; or a group selected from the group consisting of (1,3)-benzodioxolyl, (1,4)-benzodioxanyl, tetrazolyl, (2,3)-dihydrothieno[3.4-b][1.4]dioxinyl, benzo[b]furanyl, phenyl, naphthyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl, each of which optionally may be bonded via a —(CH═CH)—, —C≡C—, —(CH₂)—, —(CH₂)₂— or —(CH₂)₃— group, and each of which may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—OH, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂, —C(═O)—O—C(CH₃)₃, —NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(CH₃)—(C₂H₅), —NH—C(═O)—O—CH₃, —NH—S(═O)₂—CH₃, —NH—S(═O₂)—C₂H₅, —NH—S(═O)₂—CH(CH₃)₂, —NH—C(═O)—O—C₂H₅, —NH—C(═O)—O—C(CH₃)₃, —C(═O)—H, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃, —C(═O)—NH₂, —C(═O)—NH—CH₃, —C(═O)-nH—C₂H₅, —C(═O)—N(CH₃)₂, —C(═O)—N(C₂H₅)₂, —O-phenyl, —O-benzyl, phenyl, and benzyl; R³⁹, R⁴⁰, and R⁴¹, R⁴², R⁴³, R⁵⁰, R⁵², R⁵³, R⁵⁴, R⁵⁵, and R⁵⁶ each independently represent a group selected from the group consisting of methyl, —CF₃, —CCl₃, —CBr₃, —CHF₂, —CH₂F, —CF₂Cl, —CCl₂F, —CH₂—CN, —CH₂—O—CH₃, —CH₂—O—CF₃, —CH₂—SF₃, ethyl, —CF₂—CH₃, —CH₂—CF₃, —C₂F₅, —CH₂—CCl₃, —CH₂—CBr₃, —CHF—CF₂Cl, —CF₂—CF₂Cl, —CFCl—CF₂Cl, —CH₂—CH₂—CN, n-propyl, —CF₂—CF₂—CF₃, —CF(CF₃)₂, isopropyl, —CH₂—CH₂—CH₂—CN, —CH₂—O—CH₂—CH₃, —CH₂—CH₂—SF₃, —CH₂—CH₂—OCF₃, —CH(CH₃)—(O—CH₃), —CH(CH₃)—(S—CH₃), n-butyl, —CF₂—CF₂—CF₂—CF₃, —CH₂—CH₂—CH₂—CH₂—CN, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethylhept-4-yl, 3-methylbutyl, n-hexyl, (3,3)-dimethylbutyl, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—C₂H₅, —CH₂—CH₂—CH₂—O—CH₃, ethenyl, propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, and 3-pentenyl; or a group selected from the group consisting of 2,3-dihydro-1H-indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl, each of which optionally may be bonded via a —CH₂—O—, —CH₂—CH₂—O—, —CH₂—CH₂—O—CH₂—, —CH₂—CH(CH₃)—O—CH₂—, —(CH₂)—, —(CH₂)₂bond or —(CH₂)₃ group, and each of which may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), —OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —O—CF₃, —S—CF₃, —SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃, —C(═O)—OH, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂, and —C(═O)—O—C(CH₃)₃; or a group selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, thiazolyl, oxazolyl, and isoxazolyl, each of which optionally may be bonded via a —(CH₂)—, —(CH₂)₂— or —(CH₂)₃-group, and each of which may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—OH, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂, —C(═O)—O—C(CH₃)₃, —NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(CH₃)—(C₂H₅), —NH—C(═O)—O—CH₃, —NH—C(═O)—O—C₂H₅, —NH—C(═O)—O—C(CH₃)₃, —C(═O)—H, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃, —C(═O)—NH₂, —C(═O)—NH—CH₃, —C(═O)-nH—C₂H₅, —C(═O)—N(CH₃)₂, —C(═O)—N(C₂H₅)₂, —O-phenyl, —O-benzyl, phenyl, and benzyl; or R⁴⁰ and R⁴¹ together with the nitrogen atom to which they are attached form a group selected from the group consisting of 3-azabicyclo[3.1.1]heptyl, 6-azaspiro[2.5]octyl, 3-acabicyclo[3.2.1]octyl, 6-azabicyclo[3.3.1]heptyl, 8-acabicyclo[3.2.1]octyl, 1-oxa-2,8-diazaspiro[4.5]dec-2-enyl, azocanyl, isoindolyl, indolyl, (1,2,3,6)-tetrahydropyridinyl, (4,5,6,7)-tetrahydroisoxazolo[5.4-c]pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl, and thiomorpholinyl, wherein the heterocycloaliphatic portion may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 groups R⁵⁷; R⁵⁷ represents —NHR⁵⁸, —NR⁵⁹R⁶⁰, or an alkyl group selected from the group consisting of —CF₃, —CH₂—CF₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; R⁵⁸, R⁵⁹, and R⁶⁰ each independently represent —C(═O)—R⁶¹; or an alkyl group selected from the group consisting of —CF₃, —CH₂—CF₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; or a group selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, thiazolyl, oxazolyl, and isoxazolyl, each of which optionally may be bonded via a —(CH₂)—, —CH₂)₂— or —(CH₂)₃— group, and each of which may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —NH₂, —NO₂, —O—CF₃, —S—CF₃, —SH, —S—CH₃, —S—C₂H₅, —S—CH(CH₃)₂, —S—C(CH₃)₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, —C(═O)—OH, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —C(═O)—O—CH(CH₃)₂, —C(═O)—O—C(CH₃)₃, —NH—CH₃, —NH—C₂H₅, —NH—C(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(CH₃)—(C₂H₅), —NH—C(═O)—O—CH₃, —NH—C(═O)—O—C₂H₅, —NH—C(═O)—O—C(CH₃)₃, —C(═O)—H, —C(═O)—CH₃, —C(═O)—C₂H₅, —C(═O)—CH(CH₃)₂, —C(═O)—C(CH₃)₃, —C(═O)—NH₂, —C(═O)—NH—CH₃, —C(═O)-nH—C₂H₅, —C(═O)—N(CH₃)₂, —C(═O)—N(C₂H₅)₂, —O-phenyl, —O-benzyl, phenyl, and benzyl; and R⁶¹ represents an alkyl group selected from the group consisting of —CF₃, —CH₂—CF₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; or a salt thereof.
 6. A compound according to claim 1, wherein: n is 0, 1, or 2; R¹ represents H; F; Cl; Br; I; —CF₃; —CN; —NH₂; —OH; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)—NR²²R²³; —S(═O)₂—R²⁷; methyl; —CF₃; —CHF₂; —CH₂F; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R² represents H; F; Cl; Br; I; —CF₃; —CN; —NH₂; —OH; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)—NR²²R²³; —S(═O)₂—R²⁷; methyl; —CF₃; —CHF₂; —CH₂F; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R³ represents H; F; Cl; Br; I; —CF₃; —CN; —NH₂; —OH; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)₂—R²⁷; methyl; —CF₃; —CHF₂; —CH₂F; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R⁴ represents H; F; Cl; Br; I; —CF₃; —CN; —NH₂; —OH; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)—NR²²R²³; —S(═O)₂—R²⁷; methyl; —CF₃; —CHF₂; —CH₂F; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R⁵ represents H; F; Cl; Br; I; —CF₃; —CN; —NH₂; —OH; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷; —S(═O)—NR²²R²³; —S(═O)₂—R²⁷; methyl; —CF₃; —CHF₂; —CH₂F; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R⁶ represents hydrogen or an alkyl group selected from the group consisting of isopropyl, n-butyl, sec-butyl, isobutyl, methyl, ethyl, and n-propyl; R⁷ represents hydrogen or —OH; or R⁶ and R⁷ together with the carbon atom to which they are attached form a cycloalkyl group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; R⁸ represents —CF₃; or tert-butyl; T represents C—R³⁵; U represents C—R³⁶; V represents N, and W represents C—R³⁸; R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently represent a group selected from the group consisting of methyl, —CF₃, —CHF₂, —CH₂F, ethyl, —CF₂—CH₃, —CH₂—CF₃, —C₂F₅, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethylhept-4-yl, 3-methylbutyl, n-hexyl, (3,3)-dimethylbutyl, and ethenyl; R³⁵, R³⁶, and R³⁷ each independently represent H; —SF₅; —NO₂; —CN; —NH₂; —OH; —SH; —OR¹⁶; —SR¹⁷; —CH₂—OH; methyl; —CF₃; —CHF₂; —CH₂F; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl or tert-butyl; R³⁸ represents —SF₅; —NO₂; —CN; —NH₂; —OH; —SH; —NHR³⁹; —NR⁴⁰R⁴¹; —OR⁴²; —SR⁴³; or a group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl, each of which is bonded to the basic framework via a carbon atom of the rings thereof, and each of which may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of —CH₂—N(CH₃)₂, —CH₂—N(C₂H₅)₂, —CH₂—NH—CH₃, —CH₂—NH—C₂H₅, —N—[C(═O)—C₂H₅]phenyl, —N—[C(═O)—CH₃]phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; or a group selected from the group consisting of phenyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, and pyrimidinyl, each of which optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF₃, —SF₅, —OH, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, —O—CF₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; R⁴¹, R⁴², R⁴³, R⁴², and R⁴³, each independently represent a group selected from the group consisting of methyl, —CH₂—O—CH₃, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, (3,3)-dimethylbutyl, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—C₂H₅, and —CH₂—CH₂—CH₂—O—CH₃; or a group selected from the group consisting of 2,3-dihydro-1H-indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl, and thiomorpholinyl, each of which optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; or R⁴⁰ and R⁴¹ together with the nitrogen atom to which they are attached form a group selected from the group consisting of 3-azabicyclo[3.1.1]heptyl, 6-azaspiro[2.5]octyl, 3-acabicyclo[3.2.1]octyl, 6-azabicyclo[3.3.1]heptyl, 8-acabicyclo[3.2.1]octyl, 1-oxa-2,8-diazaspiro[4.5]dec-2-enyl, azocanyl, isoindolyl, indolyl, (1,2,3,6)-tetrahydropyridinyl, (4,5,6,7)-tetrahydroisoxazolo[5.4-c]pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl, and thiomorpholinyl, wherein the heterocycloaliphatic moiety may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 groups R⁵⁷; R⁵⁷ represents —NHR⁵⁸, —NR⁵⁹R⁶⁰, or an alkyl group selected from the group consisting of —CF₃, —CH₂—CF₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; R⁵⁸, R⁵⁹, and R⁶⁰ each independently represent —C(═O)—R⁶¹; or an alkyl group selected from the group consisting of —CF₃, —CH₂—CF₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; or an aromatic group selected from the group consisting of phenyl and naphthyl, wherein said aromatic group optionally may be bonded via a —(CH₂)—, —(CH₂)₂— or —(CH₂)₃— group, and may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF₃, —O—CH₃, —O—C₂H₅, —O—CH(CH₃)₂, —O—C(CH₃)₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; and R⁶¹ represents an alkyl group selected from the group consisting of —CF₃, —CH₂—CF₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; or a salt thereof.
 7. A compound according to claim 1, wherein: n is 0, 1, or 2; R¹ represents H; F; Cl; Br; I; methyl, ethyl, —OH; —NH₂; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³, or —(S═O)—R²⁷; R² represents H; F; Cl; Br; I; methyl, ethyl, —OH; —NH₂; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³, or —(S═O)—R²⁷; R³ represents H; F; Cl; Br; I; methyl, ethyl, —OH; —NH₂; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, -or —(S═O)—R²⁷; R⁴ represents H; F; Cl; Br; I; methyl, ethyl, —OH; —NH₂; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³, or —(S═O)—R²⁷; R⁵ represents H; F; Cl; Br; I; methyl, ethyl, —OH; —NH₂; —NH—C(═O)—R¹³; —OR¹⁶; —SR¹⁷, —S(═O)₂—NR²²R²³, or —(S═O)—R²⁷; R⁶ represents hydrogen or an alkyl group selected from the group consisting of isopropyl, n-butyl, sec-butyl, isobutyl, methyl, ethyl, and n-propyl; R⁷ represents hydrogen or —OH; R⁸ represents —CF₃; or tert-butyl; T represents C—R³⁵; U represents C—R³⁶; V represents N, and W represents C—R³⁸; R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently represent a group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and ethenyl; R³⁵, R³⁶, and R³⁷ each represent H; R³⁸ represents —NHR³⁹; —NR⁴⁰R⁴¹; —OR⁴²; or —SR⁴³; R³⁹, R⁴², and R⁴³ each independently represent a group selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl; or a group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; R⁴⁰ and R⁴¹ together with the nitrogen atom to which they are bound form a group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and azepanyl, wherein the heterocycloaliphatic moiety may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 groups R⁵⁷; and R⁵⁷ represents an alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; or a salt thereof.
 8. A compound according to claim 1, wherein: n is 1; R¹ represents H; F; Cl; Br or I; R² represents H; F; Cl; Br; I; methyl; —OH; —NH₂ or —OR¹⁶; R³ represents H; F; Cl; Br; I; —OH; —NH₂; —NH—C(═O)—R¹³, —OR¹⁶; SR¹⁷; or —S(═O)—R²⁷; R⁴ represents H; F; Cl; Br; I; methyl, —OH; —NH₂ or —OR¹⁶; R⁵ represents H; F; Cl; Br or I; R⁶ represents hydrogen or an alkyl group selected from the group consisting of isopropyl, n-butyl, sec-butyl, isobutyl, methyl, ethyl, and n-propyl; R⁷ represents hydrogen or —OH; R⁸ represents —CF₃; or tert-butyl; T represents C—R³⁵; U represents C—R³⁶; V represents N, and W represents C—R³⁸; R¹³, R¹⁶, R¹⁷, R²², R²³ and R²⁷ each independently represent a group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and ethenyl; R³⁵, R³⁶, and R³⁷ each represent H; R³⁸ represents —NHR³⁹; —NR⁴⁰R⁴¹; —OR⁴²; or —SR⁴³; R³⁹, R⁴², and R⁴³ each independently represent a group selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, and (3,3)-dimethylbutyl; or a group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which optionally may be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; R⁴⁰ and R⁴¹ together with the nitrogen atom to which they are attached form a group selected from the group comprising the group consisting pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and azepanyl, wherein the heterocycloaliphatic moiety may be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 groups R⁵⁷; and R⁵⁷ represents an alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; or a salt thereof.
 9. A compound according to claim 6, corresponding to formula Ia:

wherein D represents N; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁴² have the respective meanings given in claim 6; or a salt thereof.
 10. A compound according to claim 7, corresponding to formula Ia:

wherein D represents N; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁴² have the respective meanings given in claim 7; or a salt thereof.
 11. A compound according to claim 8, corresponding to formula Ia:

wherein D represents N; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁴² have the respective meanings given in claim 8; or a salt thereof.
 12. A compound according to claim 6, corresponding to formula Ib:

wherein D represents N; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁴² have the respective meanings given in claim 3; or a salt thereof.
 13. A compound according to claim 7, corresponding to formula Ib:

wherein D represents N; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁴² have the respective meanings given in claim 7; or a salt thereof.
 14. A compound according to claim 8, corresponding to formula Ib:

wherein D represents N; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁴² have the respective meanings given in claim 8; or a salt thereof.
 15. A compound according to claim 6, corresponding to formula Ic:

wherein D represents N; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁴² have the respective meanings given in claim 6; or a salt thereof.
 16. A compound according to claim 7, corresponding to formula Ic:

wherein D represents N; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁴² have the respective meanings given in claim 7; or a salt thereof.
 17. A compound according to claim 8, corresponding to formula Ic:

wherein D represents N; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁴² have the respective meanings given in claim 8; or a salt thereof.
 18. A compound selected from the group consisting of: [1] 2-(4-Amino-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [2] 2-(3,5-Dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [3] 2-(4-Amino-3-bromo-5-methoxyphenyl)-N-((2-(4-methyl- piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [4] 2-(3-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [5] 2-(2,4-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [6] 2-(2,6-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [7] 2-(2,5-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [8] 2-(4-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [9] 2-(4-Hydroxy-3-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [10] 2-(3,5-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [11] 2-(3,4-Difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [12] 2-(4-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [13] 2-(3-Fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [14] 2-(3,4-Diaminophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [15] N-(2-Butoxy-6-tert-butylpyridin-3-ylmethyl)- 2-(3,4-diamino-phenyl)-propionamide, [16] N-((6-tert-Butyl-2-(4-methylpiperidin-1-yl)pyridin-3- yl)methyl)-2-(3,4-diaminophenyl)propanamide, [17] N-((6-tert-Butyl-2-(cyclohexylthio)pyridin-3-yl)methyl)- 2-(3,4-diaminophenyl)propanamide, [18] 2-(4-Acetamido-3-fluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [19] 2-(3,5-Dibromo-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [20] 2-(4-Amino-3,5-dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [21] 2-(3-Brom-4-hydroxy-5-methoxyphenyl)-N-((2-(4-methyl- piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [22] 2-(4-Amino-3,5-dibromophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [23] 2-(3,5-Dibromo-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide, [24] 2-(3-Amino-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, and [25] 2-(3,5-Dibromophenyl)-N-(4-methyl-6′-trifluoromethyl- 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)acetamide [26] 2-(4-Amino-3,5-difluorophenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [28] 2-(3-Chloro-4-(methylthio)phenyl)-N-((2-(4-methylpiperidin- 1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [29] 2-(3-Chloro-4-(methylsulfonyl)phenyl)-N-((2-(4-methylpiperidin- 1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [30] 2-(3-Fluoro-4-(methylthio)phenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [31] 2-(3-Fluoro-4-(methylsulfonyl)phenyl)-N-((2-(4-methylpiperidin- 1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [33] N-(2-Fluoro-4-(1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)- pyridin-3-yl)methylamino)-1-oxopropan-2-yl)phenyl)acrylamide, [34] N-(2-Fluoro-6-iodo-4-(1-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)-pyridin-3-yl)methylamino)-1-oxopropan-2- yl)phenyl)acrylamide, [35] 2-(4-Methoxy-3,5-dimethylphenyl)-N-((2-(4-methylpiperidin- 1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [36] 2-(3,5-Difluoro-4-methoxyphenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, [37] 2-(4-Hydroxy-3,5-dimethylphenyl)-N-((2-(4-methylpiperidin- 1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide, and [38] 2-(3,5-Difluoro-4-hydroxyphenyl)-N-((2-(4-methylpiperidin-1-yl)- 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide.


19. A compound according to claim 1, wherein, in the FLIPR assay using CHO-K1 cells transfected with a human VR1 gene, said compound in a concentration below 2000 nM, causes a 50 percent displacement of capsaicin present in a concentration of 100 nM.
 20. A compound according to claim 19, wherein said compound in a concentration below 300 nM causes a 50 percent displacement of capsaicin present in a concentration of 100 nM.
 21. A compound according to claim 20, wherein said compound in a concentration below 75 nM causes a 50 percent displacement of capsaicin present in a concentration of 100 nM.
 22. A compound according to claim 21, wherein said compound in a concentration below 10 nM causes a 50 percent displacement of capsaicin present in a concentration of 100 nM.
 23. A pharmaceutical composition comprising a compound according to claim 1, and at least one pharmaceutically acceptable carrier or adjuvant.
 24. A process for producing a compound according to claim 1, said process comprising: converting a compound corresponding to formula II:

wherein R⁸, U, T, V and W have the meanings given in claim 1, m is 0, 1, 2, or 3, and R represents hydrogen or a linear or branched C₁₋₆ alkyl group, in a reaction medium, in the presence of a reducing agent, to a compound of corresponding to formula III:

wherein R⁸, U, T, V, W and m have the meanings given above, and optionally isolating or purifying the compound of formula III, converting the compound of formula III, in a reaction medium, and in the presence of diphenylphosphorylazide or of HN₃, to a compound corresponding to formula IV:

wherein R⁸, U, T, V, W and m have the respective meanings given above, and optionally isolating or purifying the compound of formula IV, converting the compound of formula IV in a reaction medium, and a) in the presence of a reducing agent, or b) in the presence of a catalyst and of hydrogen or of hydrazine, or c) in the presence of triphenylphosphine, to a compound corresponding to formula V:

wherein R⁸, U, T, V, W and m have the respective meanings given above, and optionally isolating or purifying the compound of formula V, or converting a compound corresponding to formula VI:

wherein R⁸, U, T, V, W and m have the respective meanings given above, in a reaction medium, a) in the presence of a catalyst under a blanket of hydrogen, optionally in the presence of an acid; or b) in the presence of a reducing agent, optionally in the presence of NiCl₂, to form a compound corresponding to formula V or salt thereof, and optionally isolating or purifying the compound of formula V, reacting the compound corresponding to formula V with a compound corresponding to formula VII:

wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ have the respective meanings given in claim 1, in a reaction medium, optionally in the presence of a coupling agent, and optionally in the presence of a base, or with a compound corresponding to formula VIII:

wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ have the respective meanings given above, and LG represents a leaving group, in a reaction medium, optionally in the presence of a base, to yield a compound corresponding to formula I:

wherein T, U, V, W, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ have the respective meanings given above, and n is 1, 2, 3, or 4, and optionally isolating or purifying the compound of formula I.
 25. A process according to claim 24, wherein: a compound of formula II is reacted in the presence of a reducing agent selected from the group consisting of sodium hydride, sodium, potassium hydride, lithium aluminum hydride, sodium tetrahydridoborate, and di(isobutyl)aluminum hydride; or a compound of formula IV is converted in the presence of a reducing agent selected from the group consisting of sodium hydride, potassium hydride, lithium aluminum hydride, sodium tetrahydridoborate, and di(isobutyl)aluminum hydride; or the compound of formula IV is converted in the presence of a platinum or palladium catalyst; or a compound of formula VI is converted in the presence of a palladium or platinum catalyst and of hydrochloric acid; or a compound of formula VI is converted in the presence of a reducing agent selected from the group consisting of BH₃ bullet S(CH₃)₂, lithium aluminum hydride, and sodium tetrahydridoborate; or LG represents a chlorine or bromine atom.
 26. A process for producing a compound according to claim 1, said process comprising: reacting a compound corresponding to formula X:

wherein R⁸, U, T, V, and W have the respective meanings given in claim 1, with a compound corresponding to formula VII:

wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, have the meanings given in claim 1, in a reaction medium, optionally in the presence of a coupling agent, and optionally in the presence of a base, or with a compound corresponding to formula VIII:

wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ have the respective meanings given above, and LG represents a leaving group, in a reaction medium, optionally in the presence of a base, to form a compound corresponding to formula Im:

wherein T, U, V, W, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ have the respective meanings given above, and optionally isolating or purifying the compound of formula Im.
 27. A method of treating or inhibiting pain in a subject, said method comprising administering to said subject a pharmacologically effective amount of a compound corresponding to formula I:

wherein n represents 1; R¹ represents H or F; R² represents H, F, Cl, Br, CN, NH₂, OH, OR¹⁶, CF₃, or methyl; R³ represents H, F, CH═CH₂, NH₂, OH, C(═O)—NH₂, C(═NH)NH₂, NH—C(═O)—R¹³, OR¹⁶, SR¹⁷, C(═O)—NHR¹⁸, C(═O)R²⁵, S(═O)₂—R²⁷; CF₃; or a methyl or ethyl radical which may be substituted by 1 or 2 substituents independently selected from the group consisting of OH, NH₂, NHCH₃, and N(CH₃)₂; R⁴ represents H, F, Br, I, or methyl; R⁵ represents H or F; R⁶ represents H, or a linear or branched, saturated, unsubstituted aliphatic C₁₋₁₀ group; R⁷ represents H; R⁸ represents CF₃ or an unsubstituted tert-butyl group; T represents CR³⁵; U represents CR³⁶; V represents N or CR³⁷; W represents CR³⁸; R¹³ represents phenyl, vinyl, or methyl; R¹⁶ represents methyl; R¹⁷ represents methyl; R¹⁸ represents a methyl group; a phenyl group, wherein said phenyl group may be substituted by 1 substituent independently selected from the group consisting of F, Cl, and CF₃; 2 pyridinyl; thiazolyl; or tetrahydro-2H-pyranyl; R²⁵ represents methyl; R²⁷ represents methyl; R³⁵ represents H; R³⁶ represents H; R³⁷ represents H; R³⁸ represents n-propyl, which may be substituted by 1 OCH₃ group; a phenyl group, wherein said phenyl group may be substituted by 1 or 2 substituents independently selected from the group consisting of F, Cl, O—(C₁₋₅-alkyl), (C₁₋₅-alkyl), CH₂-cyclohexyl, cyclohexyl, and cyclopentyl; NHR³⁹; NR⁴⁰R⁴¹; OR⁴²; or S—R⁴³; R³⁹ represents n-butyl; R⁴⁰ and R⁴¹ together with the nitrogen atom to which they are attached form a piperidinyl, pyrrolidinyl or morpholinyl group, which is unsubstituted or substituted by 1, 2 or 3 groups R⁵⁷; R⁴² represents n-butyl, cyclohexyl, or cyclopentyl; R⁴³ represents cyclohexyl; R⁵⁷ represents NR⁵⁹R⁶⁰ or a methyl group; R⁵⁹ represents a methyl group; and R⁶⁰ represents a methyl group.
 28. A method according to claim 27, wherein said pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; arthralgia; hyperalgesia; allodynia; causalgia; and migraine. 